TTC7A

Summary

TTC7A (tetratricopeptide repeat domain 7A, HGNC:19750) is a protein-coding gene on chromosome 2p21, encoding Tetratricopeptide repeat protein 7A (Q9ULT0). Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane. It is a selective cancer dependency (DepMap: 11.7% of cell lines).

This gene encodes a protein containing tetratricopeptide repeats. Mutations in this gene disrupt intestinal development and can cause early onset inflammatory bowel disease and intestinal atresia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 57217 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple intestinal atresia (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 1,104 total — 44 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 54
• Cancer dependency (DepMap): dependent in 11.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_020458

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19750
Approved symbol	TTC7A
Name	tetratricopeptide repeat domain 7A
Location	2p21
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1140
Ensembl gene	ENSG00000068724
Ensembl biotype	protein_coding
OMIM	609332
Entrez	57217

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 15 protein_coding, 9 protein_coding_CDS_not_defined, 6 retained_intron, 4 nonsense_mediated_decay

ENST00000319190, ENST00000394850, ENST00000409245, ENST00000409825, ENST00000440051, ENST00000441914, ENST00000461601, ENST00000474321, ENST00000484061, ENST00000484337, ENST00000491786, ENST00000496991, ENST00000651101, ENST00000651415, ENST00000652236, ENST00000652568, ENST00000698499, ENST00000698500, ENST00000698501, ENST00000698502, ENST00000698503, ENST00000698504, ENST00000895460, ENST00000895461, ENST00000895462, ENST00000895463, ENST00000895464, ENST00000895465, ENST00000895466, ENST00000937409, ENST00000937410, ENST00000937411, ENST00000956433, ENST00000956434

RefSeq mRNA: 4 — MANE Select: NM_020458 NM_001288951, NM_001288953, NM_001288955, NM_020458

CCDS: CCDS33193, CCDS74510, CCDS74511

Canonical transcript exons

ENST00000319190 — 20 exons

Exon	Start	End
ENSE00000962728	47073702	47076123
ENSE00002264384	46941224	46941725
ENSE00003469375	47049949	47050046
ENSE00003472939	47023408	47023465
ENSE00003486884	47029224	47029384
ENSE00003487233	46995136	46995199
ENSE00003506560	47024287	47024359
ENSE00003523850	46950363	46950526
ENSE00003541073	46956839	46957007
ENSE00003551179	47060769	47060971
ENSE00003557685	47005922	47006059
ENSE00003588933	46993450	46993528
ENSE00003593320	46974973	46975103
ENSE00003604779	47046315	47046431
ENSE00003623101	47011331	47011435
ENSE00003623429	46994357	46994514
ENSE00003631982	47006641	47006724
ENSE00003646965	47021862	47021979
ENSE00003650052	46978792	46978907
ENSE00003673533	47051746	47051880

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 97.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.9039 / max 1392.4229, expressed in 1816 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20123	24.6166	1807
20124	1.8483	924
20120	1.3833	771
202184	0.3045	156
20130	0.2089	58
20129	0.1542	46
20125	0.1208	46
20132	0.1049	55
20131	0.0772	35
20122	0.0498	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	97.99	gold quality
right testis	UBERON:0004534	97.06	gold quality
left testis	UBERON:0004533	97.02	gold quality
tendon of biceps brachii	UBERON:0008188	94.43	gold quality
monocyte	CL:0000576	94.10	gold quality
leukocyte	CL:0000738	94.03	gold quality
testis	UBERON:0000473	93.79	gold quality
granulocyte	CL:0000094	92.76	gold quality
thymus	UBERON:0002370	92.64	gold quality
pancreatic ductal cell	CL:0002079	92.47	gold quality
left adrenal gland cortex	UBERON:0035825	91.76	gold quality
left adrenal gland	UBERON:0001234	91.62	gold quality
right adrenal gland	UBERON:0001233	91.60	gold quality
adrenal cortex	UBERON:0001235	91.42	gold quality
right adrenal gland cortex	UBERON:0035827	91.37	gold quality
lower esophagus mucosa	UBERON:0035834	90.46	gold quality
adrenal gland	UBERON:0002369	90.06	gold quality
bone marrow cell	CL:0002092	89.45	gold quality
lymph node	UBERON:0000029	89.02	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.77	gold quality
blood	UBERON:0000178	88.73	gold quality
upper lobe of left lung	UBERON:0008952	88.62	gold quality
vermiform appendix	UBERON:0001154	88.36	gold quality
minor salivary gland	UBERON:0001830	88.35	gold quality
left lobe of thyroid gland	UBERON:0001120	88.21	gold quality
skin of leg	UBERON:0001511	87.91	gold quality
body of pancreas	UBERON:0001150	87.90	gold quality
right lobe of thyroid gland	UBERON:0001119	87.89	gold quality
saliva-secreting gland	UBERON:0001044	87.87	gold quality
spinal cord	UBERON:0002240	87.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	16.87
E-ANND-3	yes	4.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

73 targeting TTC7A, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-657	99.48	66.02	848
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-5695	99.41	67.48	1047

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 11.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 15)

• Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. (PMID:23423984)
• These data strongly suggest that TTC7A gene defects cause combined immunodeficiency with multiple intestinal atresias. (PMID:23830146)
• TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells in multiple intestinal atresia. (PMID:24292712)
• Identify loss of function mutations in TTC7A in 5 infants with very early onset inflammatory bowel disease. (PMID:24417819)
• Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency (PMID:25174867)
• identified a perfectly segregating homozygous missense mutation in TTC7A in a consanguinous Turkish pedigree causing combined immunodeficiency with mild structural intestinal defects (PMID:25745186)
• The results further demonstrate that the skin consequences of TTC7A deficiency in mice and humans are consistent with a role of TTC7A in the balance of keratinocyte maturation, proliferation and cell death processes. (PMID:27059536)
• Studies indicate that mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause a severe form of very early onset inflammatory bowel disease (PMID:27418642)
• TTC7A deficiency identified in a patient with overlapping features of tricho-hepato-enteric syndrome and multiple intestinal atresia with combined immune deficiency syndrome. (PMID:29174094)
• TTC7A Deficiency Presenting With Combined Immunodeficiency. (PMID:30350797)
• TTC7A Variants Previously Described to Cause Enteropathy Are Observed on a Single Haplotype and Appear Non-pathogenic in Pediatric Inflammatory Bowel Disease Patients. (PMID:31814065)
• The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease. (PMID:33122718)
• A Novel Homozygous TTC7A Missense Mutation Results in Familial Multiple Intestinal Atresia and Combined Immunodeficiency. (PMID:34975848)
• Pediatric Gastrointestinal Histopathology in Patients With Tetratricopeptide Repeat Domain 7A (TTC7A) Germline Mutations: A Rare Condition Leading to Multiple Intestinal Atresias, Severe Combined Immunodeficiency, and Congenital Enteropathy. (PMID:34985046)
• Actin dynamics regulation by TTC7A/PI4KIIIalpha limits DNA damage and cell death under confinement. (PMID:37390900)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttc7a	ENSDARG00000074760
mus_musculus	Ttc7	ENSMUSG00000036918
rattus_norvegicus	Ttc7a	ENSRNOG00000014879
caenorhabditis_elegans		WBGENE00021444

Paralogs (14): IFT88 (ENSG00000032742), TMTC4 (ENSG00000125247), TMTC1 (ENSG00000133687), TMTC3 (ENSG00000139324), TTC6 (ENSG00000139865), BBS4 (ENSG00000140463), TTC13 (ENSG00000143643), OGT (ENSG00000147162), CFAP70 (ENSG00000156042), TTC8 (ENSG00000165533), TTC7B (ENSG00000165914), TTC16 (ENSG00000167094), TMTC2 (ENSG00000179104), TTC34 (ENSG00000215912)

Protein

Protein identifiers

Tetratricopeptide repeat protein 7A — Q9ULT0 (reviewed: Q9ULT0)

All UniProt accessions (6): Q9ULT0, A0A8V8TMV0, G5E9G4, H0Y3V7, H7C055, H7C1P2

UniProt curated annotations — full annotation on UniProt →

Function. Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane. The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis. In the complex, plays a central role in bridging PI4KA to EFR3B and HYCC1, via direct interactions.

Subunit / interactions. Component of a phosphatidylinositol 4-kinase (PI4K) complex, composed of PI4KA, EFR3 (EFR3A or EFR3B), TTC7 (TTC7A or TTC7B) and HYCC (HYCC1 or HYCC2). Interacts with PI4KA. Interaction with PI4KA is direct. Interacts with EFR3 (EFR3A or EFR3B), interaction is direct. Interacts with HYCC (HYCC1 or HYCC2), interaction is direct. Association with the PI4K complex is strongly reduced by TMEM150A.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in epithelial cells of the intestine, thymus, and pancreas (at protein level).

Disease relevance. Gastrointestinal defects and immunodeficiency syndrome 1 (GIDID1) [MIM:243150] An autosomal recessive congenital disorder in which obstructions occur at various levels throughout the small and large intestines, ultimately leading to organ failure. Surgical interventions are palliative but do not provide long-term survival. Some patients exhibit inflammatory bowel disease (IBD), with or without intestinal atresia, and in some cases, the intestinal features are associated with either mild or severe combined immunodeficiency. The disease is caused by variants affecting the gene represented in this entry. Phenotypic variations have been observed: the mildest case show intestinal aberrations consisting of bloody diarrhea, apoptotic enterocolitis, and acute graft-versus-host disease- (GVHD)-like symptoms, but no atresias. Other patients show multiple intestinal atresias, some being associated with immunodeficiency syndrome, while other do not show immunodeficiency defects.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9ULT0-1	1	yes
Q9ULT0-3	2
Q9ULT0-4	3

RefSeq proteins (4): NP_001275880, NP_001275882, NP_001275884, NP_065191* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR045819	TTC7_N	Domain
IPR051722	Endocytosis_PI4K-reg_protein	Family

Pfam: PF13181, PF19440

UniProt features (40 total): sequence variant 19, repeat 9, modified residue 7, splice variant 3, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULT0-F1	84.59	0.61

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 (7): 51, 182, 647, 678, 679, 690, 693

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 255 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_GLYCEROLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, VANTVEER_BREAST_CANCER_ESR1_DN, GOBP_LOCALIZATION_WITHIN_MEMBRANE, MILI_PSEUDOPODIA_CHEMOTAXIS_DN

GO Biological Process (4): intracellular iron ion homeostasis (GO:0006879), hemopoiesis (GO:0030097), phosphatidylinositol phosphate biosynthetic process (GO:0046854), protein localization to plasma membrane (GO:0072659)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
cell development	1
glycerophospholipid biosynthetic process	1
protein localization to membrane	1
protein localization to cell periphery	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

728 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTC7A	HYCC1	Q9BYI3	880
TTC7A	EFR3A	Q14156	822
TTC7A	EFR3B	Q9Y2G0	768
TTC7A	PI4KA	P42356	731
TTC7A	TMEM150A	Q86TG1	724
TTC7A	HYCC2	Q8IXS8	673
TTC7A	SKIC3	Q6PGP7	667
TTC7A	LRBA	P50851	621
TTC7A	EOGT	Q5NDL2	561
TTC7A	PI4KB	P78405	556
TTC7A	IL10RA	Q13651	479
TTC7A	XIAP	P98170	451
TTC7A	MYO5B	Q9ULV0	435
TTC7A	IL10RB	Q08334	431
TTC7A	SKIC2	Q15477	431

IntAct

20 interactions, top by confidence:

A	B	Type	Score
TTC7A	UBR5	psi-mi:“MI:0915”(physical association)	0.560
LIPC	ATP4A	psi-mi:“MI:0914”(association)	0.530
TTC7A	CAMKV	psi-mi:“MI:0915”(physical association)	0.400
TTC7A	PI4K2A	psi-mi:“MI:0915”(physical association)	0.400
Hdac6	TDG	psi-mi:“MI:0914”(association)	0.350
Coro1c	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CHMP4B		psi-mi:“MI:0914”(association)	0.350
TTC7A	FANCA	psi-mi:“MI:0914”(association)	0.350
PI4KA	EFR3A	psi-mi:“MI:0914”(association)	0.350
TTC7A	HSPA8	psi-mi:“MI:0914”(association)	0.350
MCM7		psi-mi:“MI:0914”(association)	0.350
CDH1	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
MAPT	PITPNM1	psi-mi:“MI:2364”(proximity)	0.270
MAPT		psi-mi:“MI:2364”(proximity)	0.270
cya	TTC7A	psi-mi:“MI:0915”(physical association)	0.000
	TTC7A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): TTC7A (Affinity Capture-MS), TTC7A (Affinity Capture-MS), TTC7A (Affinity Capture-MS), TTC7A (Proximity Label-MS), CAMKV (Affinity Capture-MS), TTC7A (Affinity Capture-RNA), TTC7A (Affinity Capture-MS), TTC7A (Proximity Label-MS), TTC7A (Proximity Label-MS), TTC7A (Affinity Capture-MS), TTC7A (Affinity Capture-RNA), TTC7A (Affinity Capture-RNA), UBR5 (Affinity Capture-Western), TTC7A (Affinity Capture-Western), CAMKV (Affinity Capture-MS)

ESM2 similar proteins: A1A5P5, A1L1K3, A7SUU7, B4JHK2, B4NKT1, E9Q6P5, F1QN74, P09913, P50748, Q0P5W1, Q14CX7, Q294E0, Q2KI89, Q32NR4, Q32PH0, Q3U0M1, Q4R6I5, Q4R6M4, Q5R629, Q5RE52, Q5U249, Q5ZKK3, Q60462, Q68F70, Q6AYP3, Q6PA97, Q6QI44, Q80VM3, Q86TV6, Q8BGB2, Q8BH74, Q8BTZ4, Q8BWZ3, Q8C0S4, Q8CIM8, Q8GZN1, Q8IYW2, Q8JGR7, Q8K368, Q8N3P4

Diamond homologs: E9Q6P5, Q86TV6, Q8BGB2, Q9ULT0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1104 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	21
Uncertain significance	409
Likely benign	445
Benign	102

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073085	NC_000002.11:g.(?47177482)(47301062_?)del	Pathogenic
1323723	NM_020458.4(TTC7A):c.1919+1G>A	Pathogenic
140577	NM_020458.4(TTC7A):c.829C>T (p.Gln277Ter)	Pathogenic
140578	NM_020458.4(TTC7A):c.1008C>G (p.Tyr336Ter)	Pathogenic
140579	NM_020458.4(TTC7A):c.1481del (p.Gly494fs)	Pathogenic
140580	NM_020458.4(TTC7A):c.1673_1674insG (p.Leu559fs)	Pathogenic
140581	NM_020458.4(TTC7A):c.1510+105T>A	Pathogenic
1433649	NM_020458.4(TTC7A):c.1355dup (p.Met453fs)	Pathogenic
1451842	NM_020458.4(TTC7A):c.1783G>T (p.Glu595Ter)	Pathogenic
1460133	NM_020458.4(TTC7A):c.1784_1787del (p.Glu595fs)	Pathogenic
190389	NM_020458.4(TTC7A):c.764+1del	Pathogenic
190390	NM_020458.4(TTC7A):c.315_318del (p.Asn104_Tyr105insTer)	Pathogenic
190391	NM_020458.4(TTC7A):c.844-1G>T	Pathogenic
190392	NM_020458.4(TTC7A):c.1204-2A>G	Pathogenic
190393	NM_020458.4(TTC7A):c.1576C>T (p.Gln526Ter)	Pathogenic
2001826	NM_020458.4(TTC7A):c.226C>T (p.Gln76Ter)	Pathogenic
2022174	NM_020458.4(TTC7A):c.2109del (p.Met704fs)	Pathogenic
2033508	NM_020458.4(TTC7A):c.2264del (p.Ala755fs)	Pathogenic
2034849	NM_020458.4(TTC7A):c.2272A>T (p.Lys758Ter)	Pathogenic
2049714	NM_020458.4(TTC7A):c.1281_1282insTT (p.Gly428fs)	Pathogenic
2049998	NM_020458.4(TTC7A):c.1528C>T (p.Gln510Ter)	Pathogenic
2426555	NC_000002.11:g.(?47202092)(47206066_?)del	Pathogenic
2707939	NM_020458.4(TTC7A):c.1450G>T (p.Glu484Ter)	Pathogenic
2814056	NM_020458.4(TTC7A):c.499G>T (p.Glu167Ter)	Pathogenic
284147	NM_020458.4(TTC7A):c.286G>T (p.Glu96Ter)	Pathogenic
284148	NM_020458.4(TTC7A):c.1183dup (p.Gln395fs)	Pathogenic
3247142	NC_000002.11:g.(?47256343)(47256543_?)del	Pathogenic
3383390	NM_020458.4(TTC7A):c.1672dup (p.Ala558fs)	Pathogenic
3383392	NM_020458.4(TTC7A):c.1919+2dup	Pathogenic
3626176	NM_020458.4(TTC7A):c.1610_1611del (p.Tyr537fs)	Pathogenic

SpliceAI

4058 predictions. Top by Δscore:

Variant	Effect	Δscore
2:46950357:TTTCA:T	acceptor_loss	1.0000
2:46950358:TTCA:T	acceptor_loss	1.0000
2:46950359:TCA:T	acceptor_loss	1.0000
2:46950360:CA:C	acceptor_loss	1.0000
2:46950361:A:AG	acceptor_gain	1.0000
2:46950361:AGAT:A	acceptor_gain	1.0000
2:46950362:G:GT	acceptor_gain	1.0000
2:46950362:GA:G	acceptor_gain	1.0000
2:46950362:GAT:G	acceptor_gain	1.0000
2:46950362:GATG:G	acceptor_gain	1.0000
2:46950362:GATGA:G	acceptor_gain	1.0000
2:46950525:CGGT:C	donor_loss	1.0000
2:46950527:G:GC	donor_loss	1.0000
2:46950527:G:GG	donor_gain	1.0000
2:46950528:T:TC	donor_loss	1.0000
2:46957003:CAAAG:C	donor_loss	1.0000
2:46957004:AAAG:A	donor_loss	1.0000
2:46957005:AAGGT:A	donor_loss	1.0000
2:46957006:AG:A	donor_loss	1.0000
2:46957007:GGTAG:G	donor_loss	1.0000
2:46957009:T:G	donor_loss	1.0000
2:46974967:CCGCA:C	acceptor_loss	1.0000
2:46974968:CGCAG:C	acceptor_loss	1.0000
2:46974969:GCAG:G	acceptor_loss	1.0000
2:46974970:CAGG:C	acceptor_loss	1.0000
2:46974971:A:AT	acceptor_loss	1.0000
2:46974972:G:GC	acceptor_loss	1.0000
2:46975479:G:GT	donor_gain	1.0000
2:46978790:A:AG	acceptor_gain	1.0000
2:46978791:G:GG	acceptor_gain	1.0000

AlphaMissense

5603 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:46993479:G:C	R265P	0.998
2:46994373:T:C	L287P	0.998
2:46995147:C:A	P338H	0.998
2:46995174:T:C	L347P	0.998
2:46941602:C:A	R21S	0.997
2:46957007:G:C	G173R	0.997
2:46993488:T:C	L268P	0.997
2:46995165:A:T	E344V	0.997
2:46995167:G:C	A345P	0.997
2:46995171:T:C	L346P	0.997
2:46995180:T:C	L349P	0.997
2:46941603:G:C	R21P	0.996
2:46956872:G:C	G128R	0.996
2:46956873:G:A	G128D	0.996
2:46956992:G:C	A168P	0.996
2:46994385:T:C	L291P	0.996
2:46995164:G:A	E344K	0.996
2:46950399:T:C	L74P	0.995
2:46974973:G:A	G173D	0.995
2:46993476:T:C	L264P	0.995
2:46995147:C:G	P338R	0.995
2:46995177:T:C	L348P	0.995
2:46995180:T:G	L349R	0.995
2:47006013:T:C	L386P	0.995
2:46956879:T:C	L130P	0.994
2:46975062:G:C	A203P	0.994
2:46994363:G:C	A284P	0.994
2:46995146:C:T	P338S	0.994
2:46995164:G:C	E344Q	0.994
2:46995168:C:A	A345D	0.994

dbSNP variants (sampled 300 via entrez): RS1000001774 (2:46958365 C>G,T), RS1000018082 (2:47058589 T>C,G), RS1000047020 (2:46956689 C>G,T), RS1000053501 (2:46940820 G>A,C), RS1000091323 (2:47059764 C>T), RS1000097960 (2:47029435 A>G), RS1000101452 (2:46924565 C>G), RS1000118808 (2:46935059 A>G), RS1000135170 (2:47035958 G>A), RS1000137693 (2:47053826 G>A), RS1000138004 (2:46991228 C>G,T), RS1000142241 (2:46966368 A>C), RS1000165300 (2:47023552 G>C), RS1000170502 (2:47053627 A>G), RS1000177656 (2:47032495 G>A)

Disease associations

OMIM: gene MIM:609332 | disease phenotypes: MIM:243150, MIM:607594

GenCC curated gene-disease

Disease	Classification	Inheritance
gastrointestinal defects and immunodeficiency syndrome 1	Definitive	Autosomal recessive
multiple intestinal atresia	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
multiple intestinal atresia	Definitive	AR

Mondo (5): multiple intestinal atresia (MONDO:0009465), gastrointestinal defects and immunodeficiency syndrome 1 (MONDO:0800030), gastrointestinal defect and immunodeficiency syndrome (MONDO:0030831), severe combined immunodeficiency (MONDO:0015974), common variable immunodeficiency (MONDO:0015517)

Orphanet (4): Isolated multiple intestinal atresia (Orphanet:2300), Combined immunodeficiency-multiple intestinal atresia (Orphanet:436252), Severe combined immunodeficiency (Orphanet:183660), OBSOLETE: Common variable immunodeficiency (Orphanet:1572)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000316	Hypertelorism
HP:0000778	Hypoplasia of the thymus
HP:0000872	Hashimoto thyroiditis
HP:0001072	Thickened skin
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001539	Omphalocele
HP:0001561	Polyhydramnios
HP:0001629	Ventricular septal defect
HP:0001888	Decreased total lymphocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001894	Thrombocytosis
HP:0001974	Increased total leukocyte count
HP:0002205	Recurrent respiratory infections
HP:0002223	Absent eyebrow
HP:0002247	Duodenal atresia
HP:0002293	Alopecia of scalp
HP:0002566	Intestinal malrotation
HP:0002573	Hematochezia
HP:0002589	Gastrointestinal atresia
HP:0002721	Immunodeficiency
HP:0002722	Recurrent abscess formation
HP:0002960	Autoimmunity
HP:0003270	Abdominal distention
HP:0003347	Impaired lymphocyte transformation with phytohemagglutinin
HP:0003577	Congenital onset
HP:0003765	Psoriasiform dermatitis
HP:0003819	Death in childhood
HP:0004313	Decreased circulating immunoglobulin concentration

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000635_23	Response to statin therapy	2.000000e-06
GCST000824_13	Erectile dysfunction and prostate cancer treatment	5.000000e-07
GCST005023_53	Initial pursuit acceleration	5.000000e-06
GCST008156_65	Hip circumference adjusted for BMI	4.000000e-06
GCST008162_102	Hip circumference	6.000000e-06
GCST90000025_741	Appendicular lean mass	1.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008434	initial pursuit acceleration
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D017074	Common Variable Immunodeficiency	C20.673.330
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
C562441	Intestinal Atresia, Multiple (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
bufotalin	increases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
bisphenol A	decreases methylation	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
Bortezomib	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects expression	1
Benzo(a)pyrene	decreases expression	1
Doxorubicin	decreases expression	1
Folic Acid	decreases expression	1
Lead	decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	decreases expression	1
T-2 Toxin	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Acrylamide	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TV07	HAP1 TTC7A (-) 1	Cancer cell line	Male
CVCL_XU81	HAP1 TTC7A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00520494	PHASE4	COMPLETED	Efficacy and Safety of Vivaglobin® in Previously Untreated Patients With Primary Immunodeficiency
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT01946906	PHASE4	COMPLETED	The Rifaximin Study in CVID
NCT05193552	PHASE4	RECRUITING	Usage of Spirometry in Managing IgG Therapy in CVID With Airway Disease
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00168012	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IVIG-F10 in Patients With Primary Immunodeficiencies (PID)
NCT00168025	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00322556	PHASE3	COMPLETED	Safety and Efficacy of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00542997	PHASE3	COMPLETED	Study of Subcutaneous Immune Globulin in Patients Requiring IgG Replacement Therapy
NCT01884311	PHASE3	COMPLETED	Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases
NCT01963143	PHASE3	COMPLETED	Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases
NCT02247141	PHASE3	COMPLETED	A Multi-centre Open Study to Assess the Safety and Efficacy of Subgam®
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT01489618	PHASE2	TERMINATED	Prime Boost Vaccination Strategy Combining Conjugated Anti- Pneumococcal Vaccine (s0) and Polysaccharide Anti- Pneumococcal Vaccine (s4) Compared to Polysaccharide Anti- Pneumococcal Vaccine Alone (s4) In Patients With Common Variable Immunodeficiency
NCT02579967	PHASE2	RECRUITING	Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
NCT03663933	PHASE2	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation
NCT04339777	PHASE2	RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
NCT04925375	PHASE2	RECRUITING	Abatacept for the Treatment of Common Variable Immunodeficiency With Interstitial Lung Disease
NCT05593588	PHASE2	ENROLLING_BY_INVITATION	Senolytics Treatment of Interstitial Lung Disease in Common Variable Immunodeficiency
NCT06897358	PHASE2	ACTIVE_NOT_RECRUITING	Leniolisib for Immune Dysregulation in CVID
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT00263237	PHASE1	COMPLETED	STA-5326 Meslylate to Treat Gut Inflammation Associated With Common Variable Immunodeficiency
NCT00461188	Not specified	RECRUITING	Genetics of Endocrine Tumours - Familial Isolated Pituitary Adenoma - FIPA
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases