ACD

Summary

ACD (ACD shelterin complex subunit and telomerase recruitment factor, HGNC:25070) is a protein-coding gene on chromosome 16q22.1, encoding Adrenocortical dysplasia protein homolog (Q96AP0). Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. It is a selective cancer dependency (DepMap: 25.9% of cell lines).

This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I.

Source: NCBI Gene 65057 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ACD-related short telomere syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 1,430 total — 10 pathogenic, 5 likely-pathogenic (top 2% of genes corpus-wide)
• GTEx eGene: eQTL in 13 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 94
• Cancer dependency (DepMap): dependent in 25.9% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.92 (unconstrained)
• MANE Select transcript: NM_001082486

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25070
Approved symbol	ACD
Name	ACD shelterin complex subunit and telomerase recruitment factor
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	Ptop, Pip1, Tpp1, Tint1
Ensembl gene	ENSG00000102977
Ensembl biotype	protein_coding
OMIM	609377
Entrez	65057

Gene structure

Transcript identifiers

Ensembl transcripts: 59 — 22 retained_intron, 21 protein_coding, 15 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000620761

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 5, TSL 3: 1, TSL 5: 5

ENST00000620761, ENST00000219251, ENST00000602320, ENST00000602382, ENST00000602423, ENST00000602519, ENST00000602622, ENST00000602656, ENST00000602780, ENST00000602850, ENST00000602860, ENST00000602945, ENST00000695641, ENST00000695648, ENST00000695649, ENST00000695650, ENST00000695656, ENST00000695657, ENST00000695658, ENST00000695659, ENST00000695660, ENST00000695661, ENST00000695662, ENST00000695663, ENST00000695694, ENST00000695695, ENST00000695696, ENST00000695697, ENST00000695698, ENST00000695699, ENST00000695700, ENST00000695701, ENST00000695702, ENST00000695709, ENST00000695710, ENST00000695711, ENST00000695712, ENST00000695713, ENST00000695731, ENST00000695732, ENST00000695733, ENST00000695734, ENST00000695735, ENST00000695736, ENST00000896207, ENST00000896208, ENST00000938871, ENST00000938872, ENST00000957224, ENST00000957225, ENST00000957226, ENST00001003389, ENST00001003390, ENST00001011004, ENST00001011005, ENST00001011006, ENST00001011007, ENST00001066749, ENST00001100060

RefSeq mRNA: 3 — MANE Select: NM_001082486 NM_001082486, NM_001410884, NM_022914

CCDS: CCDS10842, CCDS42181, CCDS92179

Canonical transcript exons

ENST00000620761 — 12 exons

Exon	Start	End
ENSE00000844202	67659903	67660045
ENSE00001943429	67660122	67660260
ENSE00003502012	67658928	67659079
ENSE00003507372	67658720	67658816
ENSE00003527690	67659537	67659613
ENSE00003562308	67659229	67659263
ENSE00003611675	67659702	67659795
ENSE00003629179	67658555	67658641
ENSE00003676212	67659375	67659419
ENSE00003964859	67657986	67658362
ENSE00003964864	67657762	67657853
ENSE00003964866	67657512	67657684

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 94.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.8242 / max 80.1037, expressed in 1775 samples.

Highest expression (Bgee): hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex, oocyte, cerebellum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ACD is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	5.5e-07	-0.15	16:67547980:A:G
Thyroid	eqtl	4.5e-05	-0.25	16:67433729:T:C
Testis	sqtl	4.8e-04	+0.92	16:67659534:T:C
Lung	eqtl	1.3e-03	-0.16	16:67432527:T:C
Adipose Subcutaneous	eqtl	2.4e-03	-0.22	16:67945638:C:G
Colon Transverse	eqtl	2.9e-03	-0.25	16:67268745:C:T
Adipose Visceral Omentum	eqtl	5.1e-03	-0.14	16:67557486:A:G
Kidney Cortex	eqtl	8.2e-03	+1.51	16:67351347:C:T
Minor Salivary Gland	eqtl	1.8e-02	-0.41	16:67287017:C:T
Prostate	eqtl	1.9e-02	+0.77	16:66905254:C:A
Heart Atrial Appendage	eqtl	2.0e-02	+0.55	16:67955353:G:A
Muscle Skeletal	eqtl	2.8e-02	-0.09	16:67970916:T:C
Skin Sun Exposed Lower leg	eqtl	3.3e-02	+0.22	16:68639286:G:A
Pancreas	eqtl	4.7e-02	+0.24	16:67992223:T:C

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
157807	10.5687	1744
157808	2.4240	1357
157806	0.2947	149
157810	0.2744	99
157809	0.1955	57
157805	0.0669	16

Top tissues by expression

showing 100 of 291 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	94.87	gold quality
cerebellar hemisphere	UBERON:0002245	94.24	gold quality
cerebellar cortex	UBERON:0002129	94.15	gold quality
oocyte	CL:0000023	93.79	gold quality
cerebellum	UBERON:0002037	93.67	gold quality
secondary oocyte	CL:0000655	92.04	gold quality
pituitary gland	UBERON:0000007	91.44	gold quality
adenohypophysis	UBERON:0002196	91.39	gold quality
left ovary	UBERON:0002119	91.05	gold quality
right frontal lobe	UBERON:0002810	90.90	gold quality
right ovary	UBERON:0002118	90.72	gold quality
right testis	UBERON:0004534	90.66	gold quality
granulocyte	CL:0000094	90.58	gold quality
left testis	UBERON:0004533	90.55	gold quality
right uterine tube	UBERON:0001302	89.94	gold quality
body of uterus	UBERON:0009853	89.83	gold quality
endocervix	UBERON:0000458	89.54	gold quality
paraflocculus	UBERON:0005351	89.50	gold quality
cervix squamous epithelium	UBERON:0006922	89.27	silver quality
testis	UBERON:0000473	89.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.01	gold quality
cortical plate	UBERON:0005343	88.98	gold quality
lower esophagus	UBERON:0013473	88.98	gold quality
thymus	UBERON:0002370	88.95	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.80	gold quality
ovary	UBERON:0000992	88.74	gold quality
cingulate cortex	UBERON:0003027	88.57	gold quality
anterior cingulate cortex	UBERON:0009835	88.50	gold quality
ganglionic eminence	UBERON:0004023	88.38	gold quality
left uterine tube	UBERON:0001303	88.29	gold quality
prefrontal cortex	UBERON:0000451	88.26	gold quality
ectocervix	UBERON:0012249	88.11	gold quality
neocortex	UBERON:0001950	87.99	gold quality
popliteal artery	UBERON:0002250	87.99	gold quality
tibial artery	UBERON:0007610	87.99	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.97	gold quality
frontal lobe	UBERON:0016525	87.95	gold quality
frontal cortex	UBERON:0001870	87.94	gold quality
spleen	UBERON:0002106	87.86	gold quality
aorta	UBERON:0000947	87.72	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.67	gold quality
apex of heart	UBERON:0002098	87.61	gold quality
frontal pole	UBERON:0002795	87.57	gold quality
orbitofrontal cortex	UBERON:0004167	87.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.49	gold quality
ascending aorta	UBERON:0001496	87.45	gold quality
thoracic aorta	UBERON:0001515	87.44	gold quality
brain	UBERON:0000955	87.33	gold quality
central nervous system	UBERON:0001017	87.26	gold quality
nucleus accumbens	UBERON:0001882	87.21	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.17	gold quality
tibial nerve	UBERON:0001323	87.12	gold quality
cerebral cortex	UBERON:0000956	87.05	gold quality
descending thoracic aorta	UBERON:0002345	87.05	gold quality
left coronary artery	UBERON:0001626	86.93	gold quality
coronary artery	UBERON:0001621	86.87	gold quality
mucosa of stomach	UBERON:0001199	86.85	gold quality
CA1 field of hippocampus	UBERON:0003881	86.76	gold quality
forebrain	UBERON:0001890	86.71	gold quality
putamen	UBERON:0001874	86.68	gold quality
amygdala	UBERON:0001876	86.60	gold quality
right coronary artery	UBERON:0001625	86.57	gold quality
telencephalon	UBERON:0001893	86.49	gold quality
myometrium	UBERON:0001296	86.37	gold quality
middle frontal gyrus	UBERON:0002702	86.31	gold quality
mucosa of urinary bladder	UBERON:0001259	86.21	gold quality
blood	UBERON:0000178	86.19	gold quality
right lobe of thyroid gland	UBERON:0001119	86.16	gold quality
left lobe of thyroid gland	UBERON:0001120	86.10	gold quality
prostate gland	UBERON:0002367	86.09	gold quality
caudate nucleus	UBERON:0001873	86.00	gold quality
lymph node	UBERON:0000029	85.99	gold quality
adult organism	UBERON:0007023	85.98	gold quality
uterine cervix	UBERON:0000002	85.92	gold quality
embryo	UBERON:0000922	85.91	gold quality
ventricular zone	UBERON:0003053	85.87	gold quality
metanephros cortex	UBERON:0010533	85.81	gold quality
thyroid gland	UBERON:0002046	85.80	gold quality
tongue squamous epithelium	UBERON:0006919	85.80	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	85.77	gold quality
primary visual cortex	UBERON:0002436	85.72	gold quality
endometrium epithelium	UBERON:0004811	85.67	gold quality
sigmoid colon	UBERON:0001159	85.59	gold quality
occipital lobe	UBERON:0002021	85.53	gold quality
spinal cord	UBERON:0002240	85.40	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.38	gold quality
esophagus	UBERON:0001043	85.36	gold quality
body of stomach	UBERON:0001161	85.26	gold quality
temporal lobe	UBERON:0001871	85.25	gold quality
omental fat pad	UBERON:0010414	85.24	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.22	gold quality
peritoneum	UBERON:0002358	85.21	gold quality
fundus of stomach	UBERON:0001160	85.16	gold quality
substantia nigra	UBERON:0002038	85.13	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.13	gold quality
Brodmann (1909) area 10	UBERON:0013541	85.07	gold quality
midbrain	UBERON:0001891	85.06	gold quality
male germ cell	CL:0000015	85.01	silver quality
mucosa of transverse colon	UBERON:0004991	84.99	gold quality
body of pancreas	UBERON:0001150	84.97	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.68
E-CURD-10	no	45.97

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Ovary	tissue	13.1	medium
Pituitary gland	tissue	12.1
Vagina	tissue	11.6	low
Locus coeruleus	tissue	10.6
Corpus callosum	tissue	10.3
Spinal cord	tissue	10.1
Hippocampus	tissue	9.4	not detected
Postcentral gyrus	tissue	9.4
Nucleus accumbens	tissue	9.3
Bone marrow	tissue	9.3	not detected
Lymph node	tissue	9.2	low
Testis	tissue	9.2	low
Thymus	tissue	9.2
Fallopian tube	tissue	9.1	medium
Pancreas	tissue	9.0	medium
Substantia nigra	tissue	8.8
Seminal vesicle	tissue	8.6	medium
Spleen	tissue	8.4	medium
Medulla oblongata	tissue	8.3
Endometrium 1	tissue	8.2	low
Superior colliculi	tissue	8.0
Midbrain	tissue	7.6
Parathyroid gland	tissue	7.3	low
Periaqueductal gray	tissue	7.3
Pons	tissue	7.2
Tonsil	tissue	7.2	medium
Appendix	tissue	6.9	medium
Hypothalamus	tissue	6.8
Choroid plexus	tissue	6.7
Thalamus	tissue	6.7
Prostate	tissue	6.4	medium
Skeletal muscle	tissue	6.3	medium
Olfactory bulb	tissue	6.3
Putamen	tissue	6.1
Smooth muscle	tissue	6.0	medium
Lung	tissue	6.0	medium
Cerebellum	tissue	5.9	not detected
Septum	tissue	5.9
Adipose tissue	tissue	5.8	not detected
Ventral forebrain	tissue	5.7
Basal ganglia	tissue	5.6	not detected
Placenta	tissue	5.6	high
Tongue	tissue	5.5
Duodenum	tissue	5.5	medium
Hippocampal formation	tissue	5.4
Skin 1	tissue	5.3	low
Salivary gland	tissue	5.3	high
Frontal cortex	tissue	5.3
Gallbladder	tissue	5.2
Adrenal gland	tissue	5.1	high
Cervix	tissue	5.0	medium
Heart muscle	tissue	4.9	low
Amygdala	tissue	4.9
Urinary bladder	tissue	4.8	medium
Cerebral cortex	tissue	4.7	low
Motor cortex	tissue	4.7
Retrosplenial cortex	tissue	4.7
Insular cortex	tissue	4.7
Stomach 1	tissue	4.6	medium
Small intestine	tissue	4.6	low

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (16.6), Posterior thalamic nucleus (13.0), Pontine nuclei (12.8), Area postrema (12.7), Area striata (white matter) (12.7).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 4.31e-10, LOEUF 0.921, missense Z 1.07 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000620761 — one region, missense o/e 0.89. ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 25.9% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): NH-12 (-1.253), UACC-62 (-1.226), WM-115 (-1.141), 253J (-1.086), TTC-549 (-1.074), OCI-AML3 (-1.014), Malme-3M (-0.999), D341 Med (-0.979), OCUM-1 (-0.972), AGS (-0.969), OCI-AML2 (-0.966), SNU-478 (-0.953), EOL-1 (-0.949), TUHR4TKB (-0.949), IST-MES1 (-0.936).

Literature-anchored findings (GeneRIF, showing 40)

• a paper that firstly reported cloning of human TTP1 (PTOP) and its biological function at telomere. TPP1 interacts with both POT1 and TIN2, heterodimerizes with POT1 and regulates POT1 telomeric recruitment and telomere length. (PMID:15181449)
• TINT1 localized to telomeres via TIN2, where it functions as a negative regulator of telomerase-mediated telomere elongation. (PMID:15380063)
• Sequencing of ACD in 15 patients with clinical features of IMAGe syndrome, adrenal hypoplasia congenita, or congenital adrenal insufficiency revealed no coding mutations, but three novel SNPs were identified (PMID:16504561)
• coordinated interactions among TPP1, TIN2, TRF1, and TRF2 may ensure robust assembly of the telosome, telomere targeting of its subunits, and, ultimately, regulated telomere maintenance (PMID:16880378)
• findings highlight the critical role of TPP1 in telomere maintenance, and support a yin-yang model in which TPP1 and POT1 function as a unit to protect human telomeres, by both positively and negatively regulating telomerase access to telomere DNA (PMID:17237767)
• crystal structure of human TPP1 reveals an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan; TPP1 is the missing beta-subunit of human POT1 (PMID:17237768)
• REVIEW:TPP1 as a critical mediator of control of telomerase activity (PMID:17373762)
• No mutations were identified in ACD in this collection of patients with ACTH resistance phenotypes. However, the newly identified SNPs in ACD should be more closely examined for possible links to disease. (PMID:17466001)
• Tpp1 is required for the protective function of Pot1 proteins. (PMID:17632522)
• Increased expression of TPP1 correlates with resistance to radiation in human laryngeal cancer cell lines. (PMID:19424630)
• Studies indicate that TPP1 and POT1can form heterodimers that bind to the telomeric single-stranded DNA, an activity that is central for telomere end capping. (PMID:19648609)
• POT1-TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. (PMID:20094033)
• TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells. (PMID:20404094)
• Mouse gene deletion experiments revealed DNA-damage-response pathways that threaten chromosome ends and how the components of the telomeric shelterin complex prevent activation of these pathways.[Shelterin] (PMID:21209389)
• The presence of dysfunctional telomeres in chronic lymphocytic leukemia did not correlate with telomere shortening or chromatin marks deregulation but with a down-regulation of 2 shelterin genes: ACD and TINF2. (PMID:21355086)
• Human telomere POT1-TPP1 complex and its role in telomerase activity regulation. (PMID:21461822)
• Multiple POT1-TPP1 proteins coat and compact long telomeric single-stranded DNA. (PMID:21596049)
• Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication. (PMID:21829167)
• Altered expression of TPP1 in fibroblast-like synovial cells might be involved in the pathogenesis of rheumatoid arthritis. (PMID:21833529)
• Study shows that the OB-fold domain of the telomere-binding protein TPP1 recruits telomerase to telomeres through an association with the telomerase reverse transcriptase TERT; data define a potential interface for telomerase-TPP1 interaction required for telomere maintenance and implicate defective telomerase recruitment in telomerase-related disease. (PMID:22863003)
• POT1-TPP1 regulates telomeric overhang structural dynamics. (PMID:22981946)
• The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. (PMID:23103865)
• Phosphorylation of TPP1 regulates cell cycle-dependent telomerase recruitment. (PMID:23509301)
• Coordinated interactions of multiple POT1-TPP1 proteins with telomere DNA. (PMID:23616058)
• Akt regulates TPP1 homodimerization and telomere protection. (PMID:23862686)
• Telomere-binding protein TPP1 modulates telomere homeostasis and confers radioresistance to human colorectal cancer cells. (PMID:24260532)
• Suppression of telomere-binding protein TPP1 resulted in telomere dysfunction and enhanced radiation sensitivity in telomerase-negative osteosarcoma cell line. (PMID:24513288)
• G-quadruplex formation in telomeres enhances POT1/TPP1 protection against RPA binding. (PMID:24516170)
• Shelterin protein TPP 1 interacts with hTERT and recruits hTERT onto the telomeres, suggesting that TPP 1 might be involved in regulation of telomere shortening. (PMID:24721976)
• Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. (PMID:25128433)
• The shelterin component TPP1 is a binding partner and substrate for the deubiquitinating enzyme USP7. (PMID:25172512)
• The data support a causal relationship between a TPP1 mutation and bone marrow disorders in a family. (PMID:25205116)
• Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. (PMID:25233904)
• Clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785). (PMID:25505254)
• a novel ACD mutation(p.G223V)is detected; ACD is a novel gene involved in childhood pre-B acute lymphoblastic leukemia and may play a functional role in enhancing leukemia cell survival (PMID:26345285)
• Dissecting Fission Yeast Shelterin Interactions via MICro-MS Links Disruption of Shelterin Bridge to Tumorigenesis. (PMID:26365187)
• The Insertion in Fingers Domain in Human Telomerase Can Mediate Enzyme Processivity and Telomerase Recruitment to Telomeres in a TPP1-Dependent Manner. (PMID:26503784)
• POT1-TPP1 Binding and Unfolding of Telomere DNA Discriminates against Structural Polymorphism. (PMID:27173378)
• NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment. (PMID:27396482)
• Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease. (PMID:27559927)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	acd	ENSDARG00000078055
mus_musculus	Acd	ENSMUSG00000038000
rattus_norvegicus	Acd	ENSRNOG00000038973

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:87873) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 47 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal adrenal gland morphology	2
polyploidy	2
abnormal coat/ hair morphology	1
absent hair follicles	1
sparse hair	1
retarded hair growth	1
polydactyly	1
kinked tail	1
adrenal gland hypoplasia	1
absent sebaceous gland	1
hyperpigmentation	1
scaly skin	1
abnormal epidermal layer morphology	1
curly vibrissae	1
short vibrissae	1
aphagia	1
postnatal growth retardation	1
reduced fertility	1
preneoplasia	1
abnormal skin morphology	1
abnormal hair texture	1
premature death	1
abnormal kidney morphology	1
decreased circulating corticosterone level	1
small adrenal glands	1

+22 more (showing top 25).

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CTCF-DT	ncRNA	107984813
CARMIL2	protein-coding	146206
PARD6A	protein-coding	50855
RIPOR1	protein-coding	79567
ATP6V0D1-DT	ncRNA	101927837
CTCF	protein-coding	10664
AGRP	protein-coding	181
ENKD1	protein-coding	84080
C16orf86	protein-coding	388284
GFOD2	protein-coding	81577

Protein

Protein identifiers

Adrenocortical dysplasia protein homolog — Q96AP0 (reviewed: Q96AP0)

Alternative names: POT1 and TIN2-interacting protein

All UniProt accessions (19): Q96AP0, A0A8Q3SHY1, A0A8Q3SHY4, A0A8Q3SHZ0, A0A8Q3SI14, A0A8Q3SI32, A0A8Q3SI48, A0A8Q3SI54, A0A8Q3WKN9, A0A8Q3WKP4, A0A8Q3WKP5, A0A8Q3WKU3, A0A8Q3WLR8, A0A8Q3WLT1, A0A8Q3WM11, A0A8Q3WM19, R4GMR6, R4GND4, R4GNJ5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends. Without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Promotes binding of POT1 to single-stranded telomeric DNA. Modulates the inhibitory effects of POT1 on telomere elongation. The ACD-POT1 heterodimer enhances telomere elongation by recruiting telomerase to telomeres and increasing its processivity. May play a role in organogenesis.

Subunit / interactions. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1. Forms heterodimers with POT1. Identified in a complex with POT1 and single-stranded telomeric DNA. Interacts with STN1 and TINF2.

Subcellular location. Nucleus. Chromosome. Telomere.

Disease relevance. Dyskeratosis congenita, autosomal dominant, 6 (DKCA6) [MIM:616553] A form of dyskeratosis congenita, a rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. The disease is caused by variants affecting the gene represented in this entry. Dyskeratosis congenita, autosomal recessive, 7 (DKCB7) [MIM:616553] A form of dyskeratosis congenita, a rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96AP0-3	3	yes
Q96AP0-2	2

RefSeq proteins (3): NP_001075955, NP_001397813, NP_075065 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019437	TPP1/Est3	Domain
IPR028631	ACD	Family

Pfam: PF10341

UniProt features (43 total): helix 15, strand 10, sequence variant 4, region of interest 3, compositionally biased region 3, modified residue 2, chain 1, cross-link 1, splice variant 1, sequence conflict 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

28 structures by resolution:

PDB	Title	Method	Resolution (Å)
5H65	Crystal structure of human POT1 and TPP1	X-RAY DIFFRACTION	2.1
5UN7	Structure of the human POT1-TPP1 telomeric complex	X-RAY DIFFRACTION	2.1
5XYF	Crystal structure of the human TIN2-TPP1-TRF2 telomeric complex	X-RAY DIFFRACTION	2.2
2I46	Crystal structure of human TPP1	X-RAY DIFFRACTION	2.7
9Q16	Human telomerase catalytic core with shelterin protein TPP1, dGpNHpp and DNA primer …	ELECTRON MICROSCOPY	2.7
9Q12	Human telomerase catalytic core with shelterin protein TPP1 and DNA primer ending in TTAG	ELECTRON MICROSCOPY	2.8
7S1T	Structure of the human POT1-TPP1 complex	X-RAY DIFFRACTION	2.9
9Q10	Human telomerase catalytic core with shelterin protein TPP1, dTpNHpp and DNA primer …	ELECTRON MICROSCOPY	2.9
9Q11	Human telomerase catalytic core with shelterin protein TPP1, BIBR1532, dTpNHpp and DNA …	ELECTRON MICROSCOPY	2.9
5I2X	Crystal Structure of TPP1 K170del	X-RAY DIFFRACTION	3
5I2Y	Crystal Structure of TPP1 K170A	X-RAY DIFFRACTION	3
9Q14	Human telomerase catalytic core with shelterin protein TPP1, BIBR1532 and DNA primer …	ELECTRON MICROSCOPY	3
9Q0Z	Human telomerase catalytic core with shelterin protein TPP1, BIBR1532 and DNA primer …	ELECTRON MICROSCOPY	3.1
7QXA	Cryo-EM map of human telomerase-DNA-TPP1 complex (sharpened)	ELECTRON MICROSCOPY	3.2
9SHZ	Cryo-EM structure of the catalytic core of human telomerase at the elongation state of …	ELECTRON MICROSCOPY	3.2
9Q17	Class I (T1D0+) of Human telomerase catalytic core with shelterin protein TPP1, BIBR1532 …	ELECTRON MICROSCOPY	3.3
9Q18	Class II (““T0D0"”) of Human telomerase catalytic core with shelterin protein TPP1 …	ELECTRON MICROSCOPY	3.3
9QAX	The catalytic core with C2 symmetry of human telomerase dimer	ELECTRON MICROSCOPY	3.3
9Q19	Class III (T1D0) of Human telomerase catalytic core with shelterin protein TPP1 …	ELECTRON MICROSCOPY	3.4
7TRE	Human telomerase catalytic core with shelterin protein TPP1	ELECTRON MICROSCOPY	3.5
9SHY	Cryo-EM structure of the catalytic core of human telomerase at the initiation state of …	ELECTRON MICROSCOPY	3.53
9QAZ	Catalytic core 2 of dimeric human telomerase	ELECTRON MICROSCOPY	3.6
8SOJ	Cryo-EM structure of human CST bound to POT1(ESDL)/TPP1 in the absence of telomeric ssDNA	ELECTRON MICROSCOPY	3.8
9QAY	Catalytic core 1 of dimeric human telomerase	ELECTRON MICROSCOPY	3.8
9SI0	Cryo-EM structure of the catalytic core of human telomerase at the pre-termination state …	ELECTRON MICROSCOPY	3.8
7QXB	Cryo-EM map of human telomerase-DNA-TPP1-POT1 complex (sharpened map)	ELECTRON MICROSCOPY	3.9
7QXS	Cryo-EM structure of human telomerase-DNA-TPP1-POT1 complex (with POT1 side chains)	ELECTRON MICROSCOPY	3.9
8SOK	Cryo-EM structure of human CST bound to POT1(ESDL)/TPP1 in the presence of telomeric ssDNA	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96AP0-F1	63.09	0.22

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes, Other congenital disorders, Ribosomopathies, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies

Antibody reliability (HPA): IH approved · IF enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3)

Type	Positions
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	381
Phosphoserine	25, 349

Function

Pathways and Gene Ontology

Reactome pathways

9 curated (TAS) of 28; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

28 pathways:

ID	Pathway	Evidence
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence	curated
R-HSA-9670095	Inhibition of DNA recombination at telomere	curated
R-HSA-171306	Packaging Of Telomere Ends	curated
R-HSA-174411	Polymerase switching on the C-strand of the telomere	curated
R-HSA-174414	Processive synthesis on the C-strand of the telomere	curated
R-HSA-174437	Removal of the Flap Intermediate from the C-strand	curated
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis	curated
R-HSA-174430	Telomere C-strand synthesis initiation	curated
R-HSA-171319	Telomere Extension By Telomerase	curated
R-HSA-73884	Base Excision Repair	—
R-HSA-73929	Base-Excision Repair, AP Site Formation	—
R-HSA-1640170	Cell Cycle	—
R-HSA-2559583	Cellular Senescence	—
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-73886	Chromosome Maintenance	—
R-HSA-110331	Cleavage of the damaged purine	electronic
R-HSA-110329	Cleavage of the damaged pyrimidine	electronic
R-HSA-73894	DNA Repair	—
R-HSA-73927	Depurination	—
R-HSA-73928	Depyrimidination	—
R-HSA-180786	Extension of Telomeres	—
R-HSA-1500620	Meiosis	—
R-HSA-1221632	Meiotic synapsis	electronic
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine	electronic
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine	electronic
R-HSA-1474165	Reproduction	—
R-HSA-157579	Telomere Maintenance	—

MSigDB gene sets: 621 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, KOBAYASHI_EGFR_SIGNALING_24HR_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, WWTAAGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE, chr16q22, PID_TELOMERASE_PATHWAY, GOBP_VACUOLE_ORGANIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_TELOMERE_CAPPING, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT

GO Biological Process (11): telomere maintenance (GO:0000723), intracellular protein transport (GO:0006886), telomere maintenance via telomerase (GO:0007004), telomere capping (GO:0016233), protection from non-homologous end joining at telomere (GO:0031848), telomere assembly (GO:0032202), positive regulation of telomere maintenance (GO:0032206), negative regulation of telomere maintenance via telomerase (GO:0032211), protein localization to chromosome, telomeric region (GO:0070198), establishment of protein localization to telomere (GO:0070200), regulation of establishment of protein localization to telomere (GO:0070203)

GO Molecular Function (6): telomerase inhibitor activity (GO:0010521), telomeric repeat DNA binding (GO:0042162), protein-containing complex binding (GO:0044877), DNA polymerase binding (GO:0070182), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): chromosome, telomeric region (GO:0000781), nuclear telomere cap complex (GO:0000783), nucleoplasm (GO:0005654), telomerase holoenzyme complex (GO:0005697), nuclear body (GO:0016604), shelterin complex (GO:0070187), nucleus (GO:0005634)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Telomere Maintenance	3
Telomere C-strand (Lagging Strand) Synthesis	3
Depyrimidination	2
Depurination	2
Extension of Telomeres	2
Meiosis	1
Processive synthesis on the C-strand of the telomere	1
Cellular Senescence	1
Reproduction	1
Cell Cycle	1
Chromosome Maintenance	1
Cellular responses to stimuli	1

GO top-level categories

40 GO namespaces:

Category	Terms
telomere organization	2
telomerase activity	2
telomere maintenance	2
binding	2
nuclear protein-containing complex	2
DNA metabolic process	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
RNA-templated DNA biosynthetic process	1
telomere maintenance via telomere lengthening	1
telomere-telomerase complex assembly	1
telomere capping	1
telomere maintenance in response to DNA damage	1
cellular component assembly	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
negative regulation of telomere maintenance via telomere lengthening	1
negative regulation of DNA biosynthetic process	1
protein localization to chromosome	1
establishment of protein localization to chromosome	1
establishment of protein localization to telomere	1
regulation of establishment of protein localization to chromosome	1
enzyme inhibitor activity	1
sequence-specific DNA binding	1
enzyme binding	1
nucleic acid binding	1
chromosomal region	1
telomere cap complex	1
nuclear lumen	1
cellular anatomical structure	1
catalytic complex	1
ribonucleoprotein complex	1
nucleoplasm	1
intracellular membraneless organelle	1
nuclear telomere cap complex	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 17 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

17 experimentally-supported GO terms:

GO term	NS	Evidence
establishment of protein localization to telomere	BP	mutant phenotype
intracellular protein transport	BP	mutant phenotype
negative regulation of telomere maintenance via telomerase	BP	direct assay
protein localization to chromosome, telomeric region	BP	direct assay
regulation of establishment of protein localization to telomere	BP	direct assay
telomere assembly	BP	mutant phenotype
telomere capping	BP	direct assay
telomere maintenance	BP	direct assay
telomere maintenance via telomerase	BP	direct assay
chromosome, telomeric region	CC	direct assay
nuclear body	CC	direct assay
nuclear telomere cap complex	CC	direct assay
shelterin complex	CC	direct assay
DNA polymerase binding	MF	physical interaction
protein-containing complex binding	MF	physical interaction
telomerase inhibitor activity	MF	direct assay
telomeric repeat DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 716 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACD	TINF2	Q9BSI4	943
ACD	TERF1	P54274	924
ACD	TERF2	Q15554	899
ACD	POT1	Q9NUX5	878
ACD	TNKS	O95271	705
ACD	TERF2IP	Q9NYB0	630
ACD	NUPR2	A6NF83	598
ACD	WRN	Q14191	554
ACD	CTC1	Q2NKJ3	540
ACD	WNT3A	P56704	498
ACD	TERT	O14746	496
ACD	ACR	P10323	488
ACD	GNRH1	P01148	484
ACD	NOP10	Q9NPE3	470
ACD	NHP2	Q9NX24	465

IntAct

Human interaction partners of ACD in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 72 partners by confidence:

Partner	Interaction type	MIscore	Records
TINF2	physical association	0.960	15
POT1	physical association	0.930	9
TERF2	association	0.810	5
TERF1	physical association	0.780	3
KEAP1	association	0.530	1
UPF1	physical association	0.520	3
STN1	physical association	0.510	4
DBNL	physical association	0.510	2
DPYSL3	physical association	0.510	2
EIF3G	physical association	0.510	2
ENSA	physical association	0.510	2
IPO5	physical association	0.510	2
IVL	physical association	0.510	2
LRRC25	physical association	0.510	2
PDLIM2	physical association	0.510	2
RBKS	physical association	0.510	2
RGS3	physical association	0.510	2
SBDS	physical association	0.510	2
STIP1	physical association	0.510	2
STUB1	physical association	0.510	2
TBC1D10A	physical association	0.510	2
TBCD	physical association	0.510	2
TUBB2A	physical association	0.510	2
YWHAE	physical association	0.510	2
TERT	physical association	0.400	1
ECE1	physical association	0.370	6
ACTB	physical association	0.370	1
ADPRH	physical association	0.370	1
AFAP1L2	physical association	0.370	1
AIPL1	physical association	0.370	1

BioGRID (126 interactions; top human partners by supporting records): TINF2 (Two-hybrid; 16 records), POT1 (Two-hybrid; 13 records), TERF1 (Affinity Capture-MS; 5 records), FBXW7 (Affinity Capture-Western; 4 records), TERF2IP (Affinity Capture-MS; 4 records), POF1B (Affinity Capture-MS; 2 records), STK4 (Affinity Capture-MS; 2 records), UPF1 (Affinity Capture-Western; 2 records), USP7 (Affinity Capture-MS; 2 records), ACTB (Two-hybrid), ADPRH (Two-hybrid), AFAP1L2 (Two-hybrid), AIPL1 (Two-hybrid), ANKMY2 (Two-hybrid), ANXA8L1 (Two-hybrid)

SIGNOR signaling

7 signaling interactions:

A	Effect	B	Mechanism
ACD	“form complex”	POT1/ACD	binding
ACD	up-regulates	TERT	binding
NEK6	“up-regulates activity”	ACD	phosphorylation
RNF8	“up-regulates quantity by stabilization”	ACD	polyubiquitination
ACD	“down-regulates activity”	RPA2	binding
ACD	“down-regulates activity”	RPA1	binding
ACD	“down-regulates activity”	RPA3	binding

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
Rap1 complex	7	RAD50, TERF1, TERF2, TERF2IP, TINF2, ACD, POT1
Telomere-associated protein complex	6	ACD, POT1, TERF1, TERF2, TERF2IP, TINF2
TIN2 complex	4	TINF2, ACD, POT1, TERF2
TRF1-TIN2 complex	4	ACD, POT1, TERF1, TINF2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 72 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Telomere C-strand (Lagging Strand) Synthesis	5	79.3×	5e-07
Telomere Extension By Telomerase	5	47.6×	6e-06
Polymerase switching on the C-strand of the telomere	5	44.1×	7e-06
Meiotic synapsis	5	14.7×	7e-04
RHO GTPase Effectors	5	7.1×	7e-03
Cellular responses to stress	9	6.9×	2e-04
Cellular responses to stimuli	9	5.9×	6e-04
Cell Cycle	7	5.2×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of telomere maintenance via telomerase	5	55.5×	5e-06
telomere maintenance	6	24.3×	2e-05
protein folding	6	9.4×	2e-03

Disease & clinical

Genetic variants

Variant evidence for ACD: 1,430 ClinVar records (15 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,430 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	5
Uncertain significance	803
Likely benign	551
Benign	7

Top pathogenic / likely-pathogenic (15)

Showing all 15 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
208983	NM_001082486.2(ACD):c.250_252del (p.Lys84del)	Pathogenic	criteria provided, single submitter	4
992639	NM_001082486.2(ACD):c.244GAG[1] (p.Glu83del)	Pathogenic	criteria provided, single submitter	1
992640	NM_001082486.2(ACD):c.361del (p.Asp121fs)	Pathogenic	criteria provided, single submitter	1
3250428	NM_001082486.2(ACD):c.152del (p.Thr51fs)	Likely pathogenic	criteria provided, single submitter	1
3256304	NM_001082486.2(ACD):c.493+1G>T	Likely pathogenic	criteria provided, single submitter	1
4850360	NM_001082486.2(ACD):c.18del (p.Arg6fs)	Likely pathogenic	criteria provided, single submitter	1
59491	GRCh38/hg38 16q21-22.1(chr16:62179331-67770414)x1	Pathogenic	criteria provided, single submitter	1
59494	GRCh38/hg38 16q22.1(chr16:66694180-67865445)x1	Pathogenic	criteria provided, single submitter	1
992641	Single allele	Pathogenic	criteria provided, single submitter	1
4076029	GRCh37/hg19 16q22.1(chr16:67322830-69368947)x1	Pathogenic	criteria provided, single submitter	1
4279191	GRCh37/hg19 16q22.1(chr16:67538639-69583342)x1	Pathogenic	criteria provided, single submitter	1
155685	GRCh38/hg38 16q12.1-22.1(chr16:49685521-68401712)x3	Pathogenic	no assertion criteria provided	1
815823	GRCh37/hg19 16q21-22.1(chr16:65669673-70180183)x1	Pathogenic	no assertion criteria provided	1
395249	GRCh37/hg19 16q22.1(chr16:67654566-68404073)x1	Likely pathogenic	no assertion criteria provided	1
564336	GRCh37/hg19 16q22.1(chr16:67629575-67812055)x1	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ACD’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 849):

Position(s)	Effect	Δscore	Sites
16:67659535–67659536	donor_loss	1.0000	5
16:67659614–67659615	acceptor_loss	1.0000	6
16:67659700–67659701	donor_loss	1.0000	5
16:67658926–67658927	donor_loss	0.9900	5
16:67659080–67659081	acceptor_loss	0.9900	3
16:67659626	acceptor_gain	0.9900
16:67659700	donor_loss	0.9900
16:67659796–67659797	acceptor_loss	0.9900	5
16:67659901–67659902	donor_loss	0.9900	6
16:67658926	donor_loss	0.9800

AlphaMissense

404 missense substitutions predicted likely pathogenic (of 2,906 scored), across 123 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D62	8	0.964	0.989
F88	8	0.936	0.992
F123	8	0.931	0.994
F414	8	0.911	0.988
H408	8	0.852	0.952
F116	7	0.954	0.991
W12	7	0.953	0.988
W207	7	0.908	0.982
W441	7	0.904	0.965
C69	7	0.874	0.985
W81	7	0.874	0.952
D410	7	0.857	0.914
F86	7	0.830	0.962
C138	7	0.825	0.947
C192	7	0.746	0.866
D141	7	0.725	0.829
G93	6	0.866	0.960
G63	6	0.859	0.936
Y418	5	0.925	0.961
Y416	5	0.913	0.940

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	2.12e-05
Lung Adenocarcinoma (validation)	unfavorable	0.000184

Disease associations

OMIM: gene MIM:609377 | disease phenotypes: MIM:616553, MIM:614541

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
dyskeratosis congenita, autosomal dominant 6	Strong	Autosomal dominant	3
ACD-related short telomere syndrome	Strong	Semidominant
Hoyeraal-Hreidarsson syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
ACD-related short telomere syndrome	Definitive	SD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 7 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
COVID-19 research	green
Cytopenia - NOT Fanconi anaemia	green
Familial pulmonary fibrosis	green
Haematological malignancies cancer susceptibility	green
Haematological malignancies for rare disease	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Pulmonary Fibrosis, Familial	green
Adult solid tumours cancer susceptibility	amber
Childhood solid tumours	amber
Familial melanoma	amber
Inherited predisposition to acute myeloid leukaemia (AML)	amber

Mondo (5): dyskeratosis congenita, autosomal dominant 6 (MONDO:0014690), dyskeratosis congenita, autosomal recessive 7 (MONDO:0800370), chromosome 16q22 deletion syndrome (MONDO:0013798), Hoyeraal-Hreidarsson syndrome (MONDO:0018045), ACD-related short telomere syndrome (MONDO:0100569)

Orphanet (2): Hoyeraal-Hreidarsson syndrome (Orphanet:3322), 16q22 deletion syndrome (Orphanet:658540)

HPO phenotypes

showing 60 of 94 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000035	Abnormal testis morphology
HP:0000164	Abnormality of the dentition
HP:0000252	Microcephaly
HP:0000327	Hypoplasia of the maxilla
HP:0000365	Hearing impairment
HP:0000488	Retinopathy
HP:0000498	Blepharitis
HP:0000499	Abnormal eyelash morphology
HP:0000518	Cataract
HP:0000534	Abnormal eyebrow morphology
HP:0000600	Abnormality of the pharynx
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000679	Taurodontia
HP:0000704	Periodontitis
HP:0000819	Diabetes mellitus
HP:0000939	Osteoporosis
HP:0000958	Dry skin
HP:0000975	Hyperhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0001034	Hypermelanotic macule
HP:0001053	Hypopigmented skin patches
HP:0001231	Abnormal fingernail morphology
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001276	Hypertonia
HP:0001321	Cerebellar hypoplasia
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001480	Freckling
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001595	Abnormal hair morphology
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001874	Abnormality of neutrophils
HP:0001876	Pancytopenia
HP:0001881	Abnormal leukocyte morphology
HP:0001903	Anemia
HP:0001915	Aplastic anemia
HP:0001928	Abnormality of coagulation
HP:0002024	Malabsorption
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002205	Recurrent respiratory infections
HP:0002209	Sparse scalp hair
HP:0002216	Premature graying of hair
HP:0002240	Hepatomegaly
HP:0002514	Cerebral calcification
HP:0002575	Tracheoesophageal fistula
HP:0002650	Scoliosis
HP:0002664	Neoplasm
HP:0002665	Lymphoma

GWAS associations

4 associations:

Study	Trait	p-value
GCST010002_165	Refractive error	2e-14
GCST010083_276	Hemoglobin levels	1e-11
GCST002539_44	Schizophrenia	2e-8
GCST006803_78	Schizophrenia	4e-8

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004509	hemoglobin measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C536068	Hoyeraal Hreidarsson syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	decreases expression	1
jinfukang	increases expression	1
MT19c compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	increases expression	1
Caffeine	increases phosphorylation	1
Doxorubicin	decreases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Hydrogen Peroxide	affects expression	1
Lead	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Mustard Gas	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Polycyclic Aromatic Hydrocarbons	increases abundance, increases expression, affects cotreatment	1
Rotenone	decreases expression	1
Selenomethionine	affects expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Cyclosporine	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SB17	HAP1 ACD (-) 1	Cancer cell line	Male
CVCL_SB18	HAP1 ACD (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

34 trials:

NCT	Phase	Status	Title
NCT01659606	Phase 2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT04232085	Phase 2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT06817590	Phase 1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT00001496	Not specified	COMPLETED	Establishment of Normal Breast Epithelial Cell Lines From Patients at High Risk for Breast Cancer
NCT00001898	Not specified	COMPLETED	Microarray Analysis for Human Genetic Disease
NCT00026884	Not specified	RECRUITING	Collection of Serum and Tissue Samples From Patients With Biopsy-Proved or Suspected Malignant Disease
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03160274	Not specified	RECRUITING	Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions
NCT03426878	Not specified	COMPLETED	Cancer Health Assessments Reaching Many
NCT03857594	Not specified	ACTIVE_NOT_RECRUITING	Integrative Sequencing In Germline and Hereditary Tumours
NCT03973450	Not specified	UNKNOWN	Epidemiology of Pituitary Tumours: Prevalence of Associated Neoplasia
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04261972	Not specified	ACTIVE_NOT_RECRUITING	Cell-free DNA in Hereditary And High-Risk Malignancies 1
NCT04494945	Not specified	RECRUITING	Identifying and Caring for Individuals With Inherited Cancer Syndrome
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04763915	Not specified	ACTIVE_NOT_RECRUITING	Improving Care After Inherited Cancer Testing
NCT05562778	Not specified	RECRUITING	Chatbot to Maximize Hereditary Cancer Genetic Risk Assessment
NCT05664867	Not specified	RECRUITING	Implementation of Population Cancer Genetic Services in Federally Qualified Health Centers (FQHC)
NCT05721326	Not specified	COMPLETED	Sequential EHR Based Interventions to Increase Genetic Testing for Breast and Ovarian Cancer Predisposition
NCT06096688	Not specified	RECRUITING	Discovering New Targets for Colorectal and Endometrial Cancer Risk Reduction
NCT06654466	Not specified	ACTIVE_NOT_RECRUITING	Closing the GAPS: Guideline Adherence, Prevention and Surveillance in Hereditary Cancer
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06726642	Not specified	RECRUITING	CfDNA in Hereditary And High-risk Malignancies 2
NCT06914726	Not specified	ENROLLING_BY_INVITATION	Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes
NCT06927947	Not specified	RECRUITING	Navigation Interventions to Improve Cascade Genetic Testing Among Relatives of Patients With Hereditary Cancer Syndromes
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform
NCT07052266	Not specified	RECRUITING	Trial of Combined Obstetric Carrier Screening and Hereditary Cancer Screening
NCT07195071	Not specified	RECRUITING	Feasibility Trial of Combination of Obstetrical Carrier Screening and Hereditary Cancer Screening
NCT07378423	Not specified	RECRUITING	Questionnaire on Congenital Cancer Signs Through Self-Assessment
NCT07381985	Not specified	ENROLLING_BY_INVITATION	Strategy for Management of Patients With Hereditary Cancer Syndromes (HCS) in a Rural Environment
NCT07542405	Not specified	NOT_YET_RECRUITING	A Web-Based Program (Kindred) to Improve the Understanding of Genetic Cancer Risk and Cancer Genetic Testing in African American Families
NCT07626814	Not specified	COMPLETED	Increasing Uptake of Cascade Testing in Families With Familial Cancer Syndromes: A Randomized Controlled Trial of a Registry-aided Model.
NCT07695506	Not specified	NOT_YET_RECRUITING	Psychological Support and Psycho-Emotional Trajectories in Cancer Genetics.