TTC5

Summary

TTC5 (tetratricopeptide repeat domain 5, HGNC:19274) is a protein-coding gene on chromosome 14q11.2, encoding Tetratricopeptide repeat protein 5 (Q8N0Z6). Cofactor involved in the regulation of various cellular mechanisms such as actin regulation, autophagy, chromatin regulation and DNA repair. It is a selective cancer dependency (DepMap: 81.4% of cell lines).

Enables ribosome binding activity. Involved in positive regulation of mRNA catabolic process. Located in cytosol and nucleoplasm.

Source: NCBI Gene 91875 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 55 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 40
• Cancer dependency (DepMap): dependent in 81.4% of screened cell lines
• MANE Select transcript: NM_138376

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19274
Approved symbol	TTC5
Name	tetratricopeptide repeat domain 5
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	Strap
Ensembl gene	ENSG00000136319
Ensembl biotype	protein_coding
OMIM	619014
Entrez	91875

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000258821, ENST00000383029, ENST00000553828, ENST00000554157, ENST00000554992, ENST00000556592, ENST00000557379, ENST00000907488, ENST00000929046, ENST00000929047, ENST00000965890

RefSeq mRNA: 1 — MANE Select: NM_138376 NM_138376

CCDS: CCDS9546

Canonical transcript exons

ENST00000258821 — 10 exons

Exon	Start	End
ENSE00001019971	20286227	20289746
ENSE00002284618	20305887	20305951
ENSE00003492793	20301833	20301965
ENSE00003545249	20299298	20299448
ENSE00003626682	20298797	20298888
ENSE00003628213	20291983	20292127
ENSE00003632604	20295708	20295854
ENSE00003647442	20300607	20300818
ENSE00003676500	20296390	20296446
ENSE00003688377	20295312	20295526

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 97.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6332 / max 215.3042, expressed in 1661 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142009	5.6332	1661

Top tissues by expression

250 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.37	gold quality
oocyte	CL:0000023	97.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.98	gold quality
cortical plate	UBERON:0005343	87.81	gold quality
calcaneal tendon	UBERON:0003701	87.44	gold quality
buccal mucosa cell	CL:0002336	87.21	silver quality
bronchial epithelial cell	CL:0002328	86.76	gold quality
islet of Langerhans	UBERON:0000006	86.52	gold quality
oviduct epithelium	UBERON:0004804	86.36	gold quality
bronchus	UBERON:0002185	85.53	gold quality
right uterine tube	UBERON:0001302	84.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.08	gold quality
sural nerve	UBERON:0015488	83.44	gold quality
monocyte	CL:0000576	83.09	gold quality
leukocyte	CL:0000738	82.95	gold quality
embryo	UBERON:0000922	82.27	gold quality
ganglionic eminence	UBERON:0004023	82.27	gold quality
caput epididymis	UBERON:0004358	82.23	gold quality
pancreatic ductal cell	CL:0002079	82.21	gold quality
prefrontal cortex	UBERON:0000451	82.18	gold quality
ventricular zone	UBERON:0003053	81.56	gold quality
stromal cell of endometrium	CL:0002255	81.50	gold quality
fallopian tube	UBERON:0003889	81.30	gold quality
mucosa of paranasal sinus	UBERON:0005030	80.09	silver quality
tendon	UBERON:0000043	80.03	gold quality
granulocyte	CL:0000094	79.92	gold quality
colonic epithelium	UBERON:0000397	79.88	gold quality
right testis	UBERON:0004534	79.84	gold quality
adrenal tissue	UBERON:0018303	79.55	gold quality
hypothalamus	UBERON:0001898	79.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.20
E-GEOD-110499	no	198.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

44 targeting TTC5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-4724-5P	98.87	67.75	1324

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 81.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• TTC5 is a novel cofactor regulating GR function in a stress-dependent manner. (PMID:21147850)
• TTC5 and EP300 cooperate to prevent excessive accumulation of MYC in AML cells and their sensitization to cell death. (PMID:23559008)
• Human TTC5, a novel tetratricopeptide repeat domain containing gene, activates p53 and inhibits AP-1 pathway. (PMID:24091941)
• TRIP13 interference inhibited the proliferation and metastasis of thyroid cancer cells through regulating TTC5/p53 pathway and epithelial-mesenchymal transition related genes expression. (PMID:31648166)
• this study identified tetratricopeptide protein 5 (TTC5) as a tubulin-specific ribosome-associating factor that triggers cotranslational degradation of tubulin mRNAs in response to excess soluble tubulin. (PMID:31727855)
• Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability. (PMID:32439809)
• Evaluation of the Role of p53 Tumour Suppressor Posttranslational Modifications and TTC5 Cofactor in Lung Cancer. (PMID:34947995)
• TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition. (PMID:35670379)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttc5	ENSDARG00000013329
mus_musculus	Ttc5	ENSMUSG00000006288
rattus_norvegicus	Ttc5	ENSRNOG00000008850
caenorhabditis_elegans	Y37E3.1	WBGENE00021346

Protein

Protein identifiers

Tetratricopeptide repeat protein 5 — Q8N0Z6 (reviewed: Q8N0Z6)

Alternative names: Stress-responsive activator of p300

All UniProt accessions (3): Q8N0Z6, G3V3I6, H9KV81

UniProt curated annotations — full annotation on UniProt →

Function. Cofactor involved in the regulation of various cellular mechanisms such as actin regulation, autophagy, chromatin regulation and DNA repair. In non-stress conditions, interacts with cofactor JMY in the cytoplasm which prevents JMY’s actin nucleation activity and ability to activate the Arp2/3 complex. Acts as a negative regulator of nutrient stress-induced autophagy by preventing JMY’s interaction with MAP1LC3B, thereby preventing autophagosome formation. Involves in tubulin autoregulation by promoting its degradation in response to excess soluble tubulin. To do so, associates with the active ribosome near the ribosome exit tunnel and with nascent tubulin polypeptides early during their translation, triggering tubulin mRNA-targeted degradation. Following DNA damage, phosphorylated by DNA damage responsive protein kinases ATM and CHEK2, leading to its nuclear accumulation and stability. Nuclear TTC5/STRAP promotes the assembly of a stress-responsive p53/TP53 coactivator complex, which includes the coactivators JMY and p300, thereby increasing p53/TP53-dependent transcription and apoptosis. Also recruits arginine methyltransferase PRMT5 to p53/TP53 when DNA is damaged, allowing PRMT5 to methylate p53/TP53. In DNA stress conditions, also prevents p53/TP53 degradation by E3 ubiquitin ligase MDM2. Upon heat-shock stress, forms a chromatin-associated complex with heat-shock factor 1 HSF1 and p300/EP300 to stimulate heat-shock-responsive transcription, thereby increasing cell survival. Mitochondrial TTC5/STRAP interacts with ATP synthase subunit beta ATP5F1B which decreased ATP synthase activity and lowers mitochondrial ATP production, thereby regulating cellular respiration and mitochondrial-dependent apoptosis. Mitochondrial TTC5/STRAP also regulates p53/TP53-mediated apoptosis.

Subunit / interactions. Interacts with JMY and p300/EP300; the interaction occurs in the nucleus and augments the association between JMY and p300/EP300 in response to DNA damage. Forms a complex with HSF1 and p300/EP300; these interactions augment chromatin-bound HSF1 and p300/EP300 histone acetyltransferase activity, resulting in enhanced heat-shock-responsive transcription. Interacts with PRMT5; the interaction is DNA damage-dependent and promotes PRMT5 interaction with p53/TP53 and subsequent methylation. Interacts with JMY; the interaction occurs in the cytoplasm and results in the inhibition of JYM’s nucleation activity. Interacts with ribosome-coding tubulin (via 60S subunit 28S rRNA and protein uL24/RPL26) and the N-terminal of nascent tubulin polypeptide (via alpha-tubulin MREC motif and beta-tubulin MREI motif); these interactions result in tubulin mRNA-targeted degradation. Interacts with ATP5F1B; the interaction occurs in the mitochondria and results in ATP production decrease. Interacts with p53/TP53; the interaction occurs in the mitochondria and results in increased apoptosis.

Subcellular location. Nucleus. Cytoplasm. Cytoplasmic vesicle. Mitochondrion matrix.

Post-translational modifications. Phosphorylation by ATM kinase induces nuclear accumulation while interfering with nuclear export, and phosphorylation by CHEK2 kinase enhances nuclear stability.

Disease relevance. Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism (NEDCAFD) [MIM:619244] An autosomal recessive disorder characterized by global developmental delay apparent from birth, moderate-to-severe intellectual disability, poor or absent speech, and hypotonia. Most patients have variable dysmorphic facial features. Brain imaging shows corpus callosum agenesis, mild ventriculomegaly, simplified gyral pattern, and cerebral atrophy. The disease is caused by variants affecting the gene represented in this entry.

Induction. Induced upon heat-shock stress (at protein level).

RefSeq proteins (1): NP_612385* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR032076	TTC5_OB	Domain
IPR038645	TTC5_OB_sf	Homologous_superfamily

Pfam: PF16669

UniProt features (40 total): mutagenesis site 7, strand 7, repeat 6, sequence variant 6, helix 6, site 3, modified residue 2, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2XVS	X-RAY DIFFRACTION	1.8
8BPO	ELECTRON MICROSCOPY	2.8
6T59	ELECTRON MICROSCOPY	3.11
7QWS	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N0Z6-F1	93.54	0.85

Functional residue map

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

Catalytic / active sites (3): 225 (mediates interaction with n-terminal mrei motif of beta-tubulin nascent chain); 259 (mediates interaction with n-terminal mrei motif of beta-tubulin nascent chain); 147 (mediates interaction with n-terminal mrei motif of beta-tubulin nascent chain)

Post-translational modifications (2): 203, 221

Mutagenesis-validated functional residues (7):

Position	Phenotype
83	no change in interaction with n-terminal mrei motif of beta-tubulin nascent chain.
147	loss of interaction with n-terminal mrei motif of beta-tubulin nascent chain. loss of interaction with 28s rrna of ribos
225	partial loss of interaction with n-terminal mrei motif of beta-tubulin nascent chain. loss of interaction with n-termina
254	no change in interaction with 28s rrna of ribosome-coding tubulin.
259	partial loss of interaction with n-terminal mrei motif of beta-tubulin nascent chain. loss of interaction with n-termina
285	loss of interaction with 28s rrna of ribosome-coding tubulin, when associated with e-287. no change in interaction with
287	loss of interaction with 28s rrna of ribosome-coding tubulin, when associated with e-285. no change in interaction with

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6804760	Regulation of TP53 Activity through Methylation

MSigDB gene sets: 396 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_DIGESTION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, PAL_PRMT5_TARGETS_UP, MODULE_151, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, MORF_UBE2I, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN

GO Biological Process (7): DNA repair (GO:0006281), DNA damage response (GO:0006974), cellular response to starvation (GO:0009267), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of mRNA catabolic process (GO:0061014), regulation of gene expression (GO:0010468), positive regulation of RNA metabolic process (GO:0051254)

GO Molecular Function (4): DNA binding (GO:0003677), chromatin binding (GO:0003682), ribosome binding (GO:0043022), protein binding (GO:0005515)

GO Cellular Component (7): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), cytoplasmic vesicle (GO:0031410), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of TP53 Activity	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
cellular response to stress	2
binding	2
intracellular membrane-bounded organelle	2
DNA metabolic process	1
DNA damage response	1
cellular response to nutrient levels	1
response to starvation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
mRNA catabolic process	1
positive regulation of catabolic process	1
regulation of mRNA catabolic process	1
positive regulation of mRNA metabolic process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
positive regulation of macromolecule metabolic process	1
RNA metabolic process	1
regulation of RNA metabolic process	1
nucleic acid binding	1
ribonucleoprotein complex binding	1
nuclear lumen	1
mitochondrion	1
intracellular organelle lumen	1
intracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2820 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTC5	EP300	Q09472	914
TTC5	HSP90AB1	P08238	561
TTC5	HSP90AA1	P07900	557
TTC5	JMY	Q8N9B5	544
TTC5	TTC4	O95801	543
TTC5	TP53	P04637	512
TTC5	TTC39C	Q8N584	483
TTC5	MRPS9	P82933	461
TTC5	NEMF	O60524	460
TTC5	IFT56	A0AVF1	424
TTC5	CIMAP1D	Q3SX64	410
TTC5	ODAD4	Q96NG3	389
TTC5	MRPS5	P82675	364
TTC5	TRIP13	Q15645	362
TTC5	CCNB1IP1	Q9NPC3	359

IntAct

71 interactions, top by confidence:

A	B	Type	Score
CAMK2D	TTC5	psi-mi:“MI:0915”(physical association)	0.670
TUBB	PLD2	psi-mi:“MI:0914”(association)	0.640
TUBA1C	CCT6A	psi-mi:“MI:0914”(association)	0.640
TUBA1A	TUBA4A	psi-mi:“MI:0914”(association)	0.610
TTC5	CAMK2B	psi-mi:“MI:0915”(physical association)	0.560
CAMK2G	TTC5	psi-mi:“MI:0915”(physical association)	0.560
CAMK2D	TTC5	psi-mi:“MI:0915”(physical association)	0.560
CAMK2B	TTC5	psi-mi:“MI:0915”(physical association)	0.560
CAVIN1	TTC5	psi-mi:“MI:0915”(physical association)	0.560
TTC5	GOLGA6A	psi-mi:“MI:0915”(physical association)	0.560
TTC5	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
TTC5	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
HDX	TTC5	psi-mi:“MI:0915”(physical association)	0.560
TUBB2A	EML2	psi-mi:“MI:0914”(association)	0.530
TUBB2B	EML2	psi-mi:“MI:0914”(association)	0.530
STPG2	TF	psi-mi:“MI:0914”(association)	0.530
TTC5	TUBA4A	psi-mi:“MI:0914”(association)	0.530
TUBA1C	TUBA4A	psi-mi:“MI:0914”(association)	0.530
CDIPT	TTC5	psi-mi:“MI:0914”(association)	0.530
BCKDHB	DBT	psi-mi:“MI:0914”(association)	0.530
PLPPR2	METAP2	psi-mi:“MI:0914”(association)	0.530

BioGRID (90): NR3C1 (Affinity Capture-Western), TTC5 (Affinity Capture-Western), AR (Affinity Capture-Western), ESR1 (Affinity Capture-Western), TTC5 (Two-hybrid), TTC5 (Two-hybrid), MYC (Affinity Capture-Western), TTC5 (Affinity Capture-MS), TTC5 (Affinity Capture-MS), TTC5 (Affinity Capture-MS), TTC5 (Affinity Capture-MS), TTC5 (Affinity Capture-MS), TTC5 (Affinity Capture-MS), TTC5 (Affinity Capture-MS), TTC5 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8HX76, A0JP70, A4IG72, A7E3S5, A7Z052, D3ZW91, E9PY46, P57081, Q05B17, Q0P5H9, Q15061, Q32P44, Q3SZD4, Q3U821, Q499N3, Q4VBE8, Q5BK48, Q5F3K4, Q5RB07, Q5RBH8, Q5RD06, Q5XFW6, Q68EI0, Q6DFC6, Q6KAU8, Q6PFM9, Q6PGF3, Q6ZQL4, Q7ZVF0, Q7ZVR1, Q7ZY78, Q8BH57, Q8C5V5, Q8IWA0, Q8N0Z6, Q8NA23, Q8NAA4, Q8VC03, Q969R8, Q96KV7

Diamond homologs: Q0P5H9, Q5BK48, Q8N0Z6, Q99LG4

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ATM	“up-regulates activity”	TTC5	phosphorylation
TTC5	“up-regulates activity”	EP300	binding
TTC5	“up-regulates activity”	JMY	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 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
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	10	175.4×	7e-20
Transport of connexons to the plasma membrane	10	175.4×	7e-20
Gap junction trafficking and regulation	10	153.5×	3e-19
Gap junction trafficking	10	153.5×	3e-19
Post-chaperonin tubulin folding pathway	10	153.5×	3e-19
Formation of tubulin folding intermediates by CCT/TriC	10	136.4×	1e-18
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	10	131.6×	1e-18
Prefoldin mediated transfer of substrate to CCT/TriC	10	127.0×	2e-18

GO biological processes:

GO term	Partners	Fold	FDR
microtubule cytoskeleton organization	13	35.0×	9e-15
mitotic cell cycle	10	29.7×	2e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	35
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1048619	NM_138376.3(TTC5):c.599del (p.Pro200fs)	Pathogenic
1048620	NM_138376.3(TTC5):c.51+1G>A	Pathogenic
1048621	NM_138376.3(TTC5):c.629A>G (p.Tyr210Cys)	Pathogenic
1048624	NM_138376.3(TTC5):c.692C>T (p.Ala231Val)	Pathogenic
3901552	NM_138376.3(TTC5):c.496C>T (p.Arg166Ter)	Pathogenic
3062315	NM_138376.3(TTC5):c.79C>T (p.Arg27Ter)	Likely pathogenic
3576483	NM_138376.3(TTC5):c.631dup (p.Ala211fs)	Likely pathogenic

SpliceAI

2824 predictions. Top by Δscore:

Variant	Effect	Δscore
12:15883535:TTCTA:T	acceptor_loss	1.0000
12:15883536:TCTAG:T	acceptor_loss	1.0000
12:15883537:CTAGA:C	acceptor_loss	1.0000
12:15883538:TAG:T	acceptor_loss	1.0000
12:15883673:CAGC:C	donor_gain	1.0000
12:15883674:AGC:A	donor_gain	1.0000
12:15883675:GC:G	donor_gain	1.0000
12:15883675:GCG:G	donor_gain	1.0000
12:15883677:G:GG	donor_gain	1.0000
12:15889920:A:AG	acceptor_gain	1.0000
12:15889923:TTTA:T	acceptor_loss	1.0000
12:15889924:TTA:T	acceptor_loss	1.0000
12:15889925:TA:T	acceptor_loss	1.0000
12:15889926:A:AG	acceptor_gain	1.0000
12:15889927:G:GT	acceptor_gain	1.0000
12:15889927:GC:G	acceptor_gain	1.0000
12:15889927:GCA:G	acceptor_gain	1.0000
12:15889927:GCAA:G	acceptor_gain	1.0000
12:15889927:GCAAA:G	acceptor_gain	1.0000
12:15890008:AG:A	donor_loss	1.0000
12:15890009:GG:G	donor_loss	1.0000
12:15890011:T:G	donor_loss	1.0000
12:15890040:T:G	donor_gain	1.0000
12:15890591:TTTCA:T	acceptor_loss	1.0000
12:15890592:TTCA:T	acceptor_loss	1.0000
12:15890594:CAG:C	acceptor_loss	1.0000
12:15890595:A:AG	acceptor_gain	1.0000
12:15890595:A:T	acceptor_loss	1.0000
12:15890596:G:GG	acceptor_gain	1.0000
12:15890596:GGAT:G	acceptor_gain	1.0000

AlphaMissense

2860 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:20298880:C:A	G186W	0.999
14:20298879:C:T	G186E	0.998
14:20296395:C:G	A231P	0.997
14:20298799:C:G	A213P	0.997
14:20298880:C:G	G186R	0.997
14:20298880:C:T	G186R	0.997
14:20299330:A:T	V172D	0.997
14:20299343:C:G	A168P	0.997
14:20298879:C:A	G186V	0.996
14:20300674:C:T	G110D	0.996
14:20292119:C:T	G356D	0.995
14:20298819:G:T	A206D	0.995
14:20298820:C:G	A206P	0.995
14:20299334:C:G	A171P	0.995
14:20299353:A:C	S164R	0.995
14:20299353:A:T	S164R	0.995
14:20299355:T:G	S164R	0.995
14:20300638:G:T	A122D	0.995
14:20300687:A:G	W106R	0.995
14:20300687:A:T	W106R	0.995
14:20292035:A:T	V384E	0.994
14:20295803:C:G	A250P	0.994
14:20298808:A:C	Y210D	0.994
14:20299333:G:T	A171D	0.994
14:20295354:C:T	G339E	0.993
14:20296394:G:T	A231E	0.993
14:20300675:C:G	G110R	0.993
14:20300720:C:G	A95P	0.993
14:20298811:C:G	A209P	0.992
14:20299301:A:G	W182R	0.992

dbSNP variants (sampled 300 via entrez): RS1000027711 (14:20302313 T>C), RS1000083352 (14:20289129 T>TG), RS1000390776 (14:20306660 G>A,T), RS1000414367 (14:20288876 G>A), RS1000468637 (14:20289082 A>C,G), RS1000596023 (14:20293357 G>A), RS1000608 (14:20294847 A>C,G,T), RS1000615932 (14:20301527 A>C), RS1000629967 (14:20300280 T>C), RS1000724311 (14:20287582 T>C), RS1001154996 (14:20287349 A>C), RS1001513044 (14:20296791 T>C), RS1001623603 (14:20288621 G>T), RS1001731604 (14:20288024 G>A), RS1001963877 (14:20296589 C>T)

Disease associations

OMIM: gene MIM:619014 | disease phenotypes: MIM:619244

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

Mondo (2): neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism (MONDO:0030999), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (0):

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000294	Low anterior hairline
HP:0000307	Pointed chin
HP:0000322	Short philtrum
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000448	Prominent nose
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000958	Dry skin
HP:0001007	Hirsutism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001274	Agenesis of corpus callosum
HP:0001344	Absent speech
HP:0002059	Cerebral atrophy
HP:0002224	Woolly hair
HP:0002352	Leukoencephalopathy
HP:0002360	Sleep disturbance
HP:0002553	Highly arched eyebrow
HP:0002808	Kyphosis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006136_11	Alzheimer’s disease progression score	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006514	Alzheimer’s disease biomarker measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression, increases expression	1
triphenyl phosphate	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.