VIPAS39

Summary

VIPAS39 (VPS33B interacting protein, apical-basolateral polarity regulator, spe-39 homolog, HGNC:20347) is a protein-coding gene on chromosome 14q24.3, encoding Spermatogenesis-defective protein 39 homolog (Q9H9C1). Proposed to be involved in endosomal maturation implicating in part VPS33B.

Involved in endosome to lysosome transport and intracellular protein transport. Acts upstream of or within collagen metabolic process and peptidyl-lysine hydroxylation. Located in Golgi apparatus and endosome. Part of vesicle tethering complex. Implicated in arthrogryposis, renal dysfunction, and cholestasis 2.

Source: NCBI Gene 63894 — RefSeq curated summary.

At a glance

• Gene–disease (curated): arthrogryposis, renal dysfunction, and cholestasis 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 385 total — 20 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 55
• MANE Select transcript: NM_001193315

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20347
Approved symbol	VIPAS39
Name	VPS33B interacting protein, apical-basolateral polarity regulator, spe-39 homolog
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	VIPAR, VPS16B, SPE-39, SPE39, hSPE-39
Ensembl gene	ENSG00000151445
Ensembl biotype	protein_coding
OMIM	613401
Entrez	63894

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 22 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000327028, ENST00000343765, ENST00000448935, ENST00000553576, ENST00000553691, ENST00000553888, ENST00000555854, ENST00000556412, ENST00000556909, ENST00000557466, ENST00000557658, ENST00000897625, ENST00000897626, ENST00000897627, ENST00000897628, ENST00000897629, ENST00000897630, ENST00000897631, ENST00000951346, ENST00000951347, ENST00000951348, ENST00000951349, ENST00000951350, ENST00000951351, ENST00000951352, ENST00000951353

RefSeq mRNA: 19 — MANE Select: NM_001193315 NM_001193314, NM_001193315, NM_001193316, NM_001193317, NM_001400324, NM_001400325, NM_001400326, NM_001400327, NM_001400330, NM_001400331, NM_001400332, NM_001400333, NM_001400334, NM_001400335, NM_001400336, NM_001400337, NM_001400338, NM_001400339, NM_022067

CCDS: CCDS53905, CCDS9862

Canonical transcript exons

ENST00000557658 — 20 exons

Exon	Start	End
ENSE00000999620	77429681	77429767
ENSE00000999621	77435259	77435393
ENSE00000999622	77434262	77434303
ENSE00000999635	77433842	77433931
ENSE00000999636	77429006	77429095
ENSE00001230817	77428370	77428474
ENSE00001366586	77426675	77427636
ENSE00002457121	77457495	77457601
ENSE00003463950	77454010	77454102
ENSE00003509757	77441066	77441093
ENSE00003510886	77442560	77442662
ENSE00003528246	77444249	77444341
ENSE00003536018	77451187	77451333
ENSE00003537589	77449293	77449357
ENSE00003573708	77453299	77453401
ENSE00003596606	77449714	77449752
ENSE00003623593	77437808	77437881
ENSE00003631445	77443119	77443152
ENSE00003653304	77448494	77448550
ENSE00003664913	77435844	77435919

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 89.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.6452 / max 138.0397, expressed in 1812 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144228	21.6452	1812

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	89.33	gold quality
ganglionic eminence	UBERON:0004023	88.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.97	gold quality
tendon of biceps brachii	UBERON:0008188	87.87	gold quality
mucosa of stomach	UBERON:0001199	87.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.13	gold quality
adrenal tissue	UBERON:0018303	86.84	gold quality
calcaneal tendon	UBERON:0003701	86.74	gold quality
popliteal artery	UBERON:0002250	86.29	gold quality
tibial artery	UBERON:0007610	86.29	gold quality
stromal cell of endometrium	CL:0002255	86.26	gold quality
descending thoracic aorta	UBERON:0002345	86.07	gold quality
tendon	UBERON:0000043	86.03	gold quality
granulocyte	CL:0000094	85.72	gold quality
aorta	UBERON:0000947	85.61	gold quality
left ovary	UBERON:0002119	85.56	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.42	gold quality
right ovary	UBERON:0002118	85.31	gold quality
right coronary artery	UBERON:0001625	85.30	gold quality
lower esophagus	UBERON:0013473	85.27	gold quality
lower esophagus muscularis layer	UBERON:0035833	85.27	gold quality
monocyte	CL:0000576	85.21	gold quality
left coronary artery	UBERON:0001626	85.19	gold quality
leukocyte	CL:0000738	85.05	gold quality
mononuclear cell	CL:0000842	85.03	gold quality
thoracic aorta	UBERON:0001515	84.95	gold quality
right adrenal gland	UBERON:0001233	84.93	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.90	gold quality
ascending aorta	UBERON:0001496	84.87	gold quality
rectum	UBERON:0001052	84.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	199.77
E-ANND-3	yes	4.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

64 targeting VIPAS39, 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-513A-5P	100.00	69.77	2465
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-4695-5P	99.06	64.87	1151

Literature-anchored findings (GeneRIF, showing 9)

• SPE-39 homologues are present in RAB5-, RAB7-, and RAB11-positive endosomes where they play a conserved role in lysosomal delivery and probably function via their interaction with the core HOPS complex. (PMID:19109425)
• SPE-39 has an inhibitory effect due to tyrosine phosphorylation and ubiquitination on the function of Vps33B in the EGF-stimulated cells (PMID:22677173)
• VPS16B, similar to its binding partner VPS33B, is essential for megakaryocyte and platelet alpha-granule biogenesis. (PMID:23002115)
• Our data suggest that the ARC syndrome may result through impaired VIPAS39/SPE-39 and Vps33b-dependent endosomal maturation or fusion. (PMID:23918659)
• Genetic studies showed a homozygous mutation in the VIPAS39 gene. Making the definite diagnosis of the syndrome is important, while increased risk of mutation in other siblings highlights the importance of prenatal diagnosis. (PMID:26808426)
• A likely causal mutation was identified in the majority (61%), spanning many genes including ones that have only rarely been reported to cause cholestatic liver disease, e.g. TJP2 and VIPAS39 (PMID:28039895)
• Mechanism of platelet alpha-granule biogenesis: study of cargo transport and the VPS33B-VPS16B complex in a model system. (PMID:31501156)
• The Rab-binding module of FERARI (factors for endosome recycling and Rab interactions) consists of Rab11FIP5 and rabenosyn-5, while the SNARE-interacting module comprises VPS45 and VIPAS39. (PMID:31988382)
• The Sec1-Munc18 protein VPS33B forms a uniquely bidirectional complex with VPS16B. (PMID:37062417)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vipas39	ENSDARG00000103690
mus_musculus	Vipas39	ENSMUSG00000021038
rattus_norvegicus	Vipas39	ENSRNOG00000049223
drosophila_melanogaster	Vps16B	FBGN0039702
caenorhabditis_elegans		WBGENE00004975

Protein

Protein identifiers

Spermatogenesis-defective protein 39 homolog — Q9H9C1 (reviewed: Q9H9C1)

Alternative names: VPS33B-interacting protein in apical-basolateral polarity regulator, VPS33B-interacting protein in polarity and apical restriction

All UniProt accessions (4): Q9H9C1, G3V4K3, G3V549, Q6IA61

UniProt curated annotations — full annotation on UniProt →

Function. Proposed to be involved in endosomal maturation implicating in part VPS33B. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical RAB11A-dependent recycling pathway and in the maintenance of the apical-basolateral polarity. May play a role in lysosomal trafficking, probably via association with the core HOPS complex in a discrete population of endosomes; the functions seems to be independent of VPS33B. May play a role in vesicular trafficking during spermatogenesis. May be involved in direct or indirect transcriptional regulation of E-cadherin.

Subunit / interactions. Interacts with VPS33B. Associates with the homotypic fusion and vacuole protein sorting (HOPS) complex; impaired by VPS33B. A possible interaction with VPS33A is reported conflictingly. Interacts with RAB11A.

Subcellular location. Cytoplasm. Cytoplasmic vesicle. Early endosome. Recycling endosome. Late endosome.

Disease relevance. Arthrogryposis, renal dysfunction and cholestasis syndrome 2 (ARCS2) [MIM:613404] A multisystem disorder, characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase activity. Platelet dysfunction is common. The disease is caused by variants affecting the gene represented in this entry. In liver, CEACAM5 and ABCB11 are mislocalized and E-cadherin expression is decreased.

Similarity. Belongs to the SPE39 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H9C1-1	1	yes
Q9H9C1-2	2

RefSeq proteins (19): NP_001180243, NP_001180244, NP_001180245, NP_001180246, NP_001387253, NP_001387254, NP_001387255, NP_001387256, NP_001387259, NP_001387260, NP_001387261, NP_001387262, NP_001387263, NP_001387264, NP_001387265, NP_001387266, NP_001387267, NP_001387268, NP_071350 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006925	Vps16_C	Domain
IPR038132	Vps16_C_sf	Homologous_superfamily
IPR040057	Spe-39	Family

Pfam: PF04840

UniProt features (16 total): modified residue 6, compositionally biased region 3, region of interest 2, chain 1, splice variant 1, sequence variant 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H9C1-F1	78.66	0.65

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 (6): 130, 132, 21, 117, 121, 124

Mutagenesis-validated functional residues (1):

Position	Phenotype
213	disrupts endodsomal colocalization with vps33b.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 288 (showing top): GOBP_LYSOSOMAL_TRANSPORT, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_VESICLE_ORGANIZATION, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_MEMBRANE_FUSION, GOBP_VACUOLAR_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MALE_GAMETE_GENERATION, GOBP_MACROAUTOPHAGY, GOBP_PHAGOLYSOSOME_ASSEMBLY, GOBP_PEPTIDYL_LYSINE_MODIFICATION, chr14q24, GOBP_PHAGOSOME_MATURATION

GO Biological Process (11): intracellular protein transport (GO:0006886), vacuolar transport (GO:0007034), spermatogenesis (GO:0007283), endosome to lysosome transport (GO:0008333), peptidyl-lysine hydroxylation (GO:0017185), cell differentiation (GO:0030154), collagen fibril organization (GO:0030199), collagen metabolic process (GO:0032963), post-translational protein modification (GO:0043687), phagosome-lysosome fusion (GO:0090385), protein transport (GO:0015031)

GO Molecular Function (2): protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (8): cytoplasm (GO:0005737), endosome (GO:0005768), early endosome (GO:0005769), late endosome (GO:0005770), Golgi apparatus (GO:0005794), recycling endosome (GO:0055037), vesicle tethering complex (GO:0099023), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endosome	3
intracellular protein localization	2
intracellular transport	2
binding	2
endomembrane system	2
cytoplasm	2
protein transport	1
developmental process involved in reproduction	1
male gamete generation	1
lysosomal transport	1
intercellular transport	1
vesicle-mediated transport	1
protein hydroxylation	1
peptidyl-lysine modification	1
cellular developmental process	1
extracellular matrix organization	1
metabolic process	1
protein modification process	1
phagolysosome assembly	1
vesicle fusion	1
transport	1
establishment of protein localization	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasmic vesicle	1
intracellular membrane-bounded organelle	1
protein-containing complex	1
intracellular vesicle	1

Protein interactions and networks

STRING

1074 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VIPAS39	VPS33B	Q9H267	999
VIPAS39	VPS33A	Q96AX1	963
VIPAS39	RAB11A	P24410	867
VIPAS39	VPS45	Q9NRW7	806
VIPAS39	STX12	Q86Y82	773
VIPAS39	STX8	Q9UNK0	712
VIPAS39	VPS16	Q9H269	709
VIPAS39	NBEAL2	Q6ZNJ1	705
VIPAS39	RAB11FIP5	Q9BXF6	694
VIPAS39	STX7	O15400	683
VIPAS39	CEACAM5	P06731	650
VIPAS39	VPS18	Q9P253	623
VIPAS39	VPS11	Q9H270	620
VIPAS39	VPS8	Q8N3P4	599
VIPAS39	VPS39	Q96JC1	585

IntAct

87 interactions, top by confidence:

A	B	Type	Score
VPS33B	VIPAS39	psi-mi:“MI:0915”(physical association)	0.980
VIPAS39	VPS33B	psi-mi:“MI:0915”(physical association)	0.980
VIPAS39	VPS33B	psi-mi:“MI:0403”(colocalization)	0.980
CCDC22	CCDC93	psi-mi:“MI:0914”(association)	0.960
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.790

BioGRID (81): VIPAS39 (Two-hybrid), VIPAS39 (Two-hybrid), VPS33B (Affinity Capture-Western), VIPAS39 (Affinity Capture-Western), VPS33B (Affinity Capture-Western), VIPAS39 (Affinity Capture-Western), VIPAS39 (Affinity Capture-MS), VIPAS39 (Affinity Capture-MS), VIPAS39 (Affinity Capture-MS), VIPAS39 (Affinity Capture-MS), VIPAS39 (Affinity Capture-MS), VIPAS39 (Affinity Capture-MS), VIPAS39 (Two-hybrid), VIPAS39 (Proximity Label-MS), VIPAS39 (Proximity Label-MS)

ESM2 similar proteins: A1A4I9, A5D796, A5PJZ5, A7S2N8, A9ULY7, B0F9L4, B2GV24, F4HQ84, F4IDS7, O60308, O75694, O75717, O94874, P32780, P37199, P59328, Q14CX7, Q1RMS6, Q28HX4, Q4R367, Q5R822, Q5RBW9, Q5ZL91, Q5ZMG1, Q66HC5, Q6DDM4, Q6NX12, Q6P3X3, Q6PGY6, Q7TQK1, Q7ZU29, Q7ZX96, Q8BGQ1, Q8BJ71, Q8BWZ3, Q8CCJ3, Q8JGR7, Q8N1F7, Q8R3N6, Q8WVM7

Diamond homologs: A5D796, Q5PQN6, Q5TYV4, Q8BGQ1, Q9H9C1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
VIPAS39	“form complex”	“CHEVI complex”	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
Collagen biosynthesis and modifying enzymes	7	35.1×	2e-07
ECM proteoglycans	5	22.1×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
collagen fibril organization	8	42.8×	4e-09
vesicle-mediated transport	5	11.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	10
Uncertain significance	138
Likely benign	115
Benign	50

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075753	NM_001193315.2(VIPAS39):c.484C>T (p.Arg162Ter)	Pathogenic
111	NM_001193315.2(VIPAS39):c.535C>T (p.Gln179Ter)	Pathogenic
112	NM_001193315.2(VIPAS39):c.749_753del (p.Thr250fs)	Pathogenic
113	NM_001193315.2(VIPAS39):c.658C>T (p.Arg220Ter)	Pathogenic
114	NM_001193315.2(VIPAS39):c.871C>T (p.Gln291Ter)	Pathogenic
115	NM_001193315.2(VIPAS39):c.2T>G (p.Met1Arg)	Pathogenic
1701817	NM_001193315.2(VIPAS39):c.177_179delinsAAA (p.Trp59_Ser60delinsTer)	Pathogenic
1701818	NM_001193315.2(VIPAS39):c.1141C>T (p.Arg381Ter)	Pathogenic
1924536	NM_001193315.2(VIPAS39):c.643C>T (p.Arg215Ter)	Pathogenic
2003056	NM_001193315.2(VIPAS39):c.247G>T (p.Glu83Ter)	Pathogenic
2119376	NM_001193315.2(VIPAS39):c.682del (p.Ile228fs)	Pathogenic
2572863	NM_001193315.2(VIPAS39):c.808C>T (p.Arg270Ter)	Pathogenic
3639127	NM_001193315.2(VIPAS39):c.559G>T (p.Glu187Ter)	Pathogenic
3658234	NM_001193315.2(VIPAS39):c.814G>T (p.Glu272Ter)	Pathogenic
4292097	NM_001193315.2(VIPAS39):c.344-2A>G	Pathogenic
4723985	NM_001193315.2(VIPAS39):c.398del (p.Pro133fs)	Pathogenic
4812898	NM_001193315.2(VIPAS39):c.837-2A>G	Pathogenic
522399	NM_001193315.2(VIPAS39):c.1184G>A (p.Trp395Ter)	Pathogenic
635326	NM_001193315.2(VIPAS39):c.20del (p.Asp7fs)	Pathogenic
635327	NM_001193315.2(VIPAS39):c.1179+1G>A	Pathogenic
2582752	NM_001193315.2(VIPAS39):c.1048-1G>T	Likely pathogenic
2690775	NM_001193315.2(VIPAS39):c.463_464del (p.Trp155fs)	Likely pathogenic
3377487	NM_001193315.2(VIPAS39):c.1048-1G>A	Likely pathogenic
3576809	NM_001193315.2(VIPAS39):c.837-2A>C	Likely pathogenic
3576827	NM_001193315.2(VIPAS39):c.166C>T (p.Arg56Ter)	Likely pathogenic
3576828	NM_001193315.2(VIPAS39):c.157_160del (p.Asp53fs)	Likely pathogenic
3639506	NM_001193315.2(VIPAS39):c.343+1G>A	Likely pathogenic
522398	NM_001193315.2(VIPAS39):c.677A>G (p.His226Arg)	Likely pathogenic
594337	NM_001193315.2(VIPAS39):c.734+2T>C	Likely pathogenic
627536	NM_001193315.2(VIPAS39):c.618_626dup (p.Arg206_Leu208dup)	Likely pathogenic

SpliceAI

3046 predictions. Top by Δscore:

Variant	Effect	Δscore
14:77427632:ATTTG:A	acceptor_gain	1.0000
14:77427633:TTTG:T	acceptor_gain	1.0000
14:77427634:TTG:T	acceptor_gain	1.0000
14:77427634:TTGCT:T	acceptor_loss	1.0000
14:77427635:TG:T	acceptor_gain	1.0000
14:77427637:C:CC	acceptor_gain	1.0000
14:77427637:CT:C	acceptor_loss	1.0000
14:77427638:T:C	acceptor_loss	1.0000
14:77427639:G:C	acceptor_gain	1.0000
14:77427639:G:GC	acceptor_gain	1.0000
14:77428361:G:C	donor_gain	1.0000
14:77428369:CCGAG:C	donor_gain	1.0000
14:77428483:C:CT	acceptor_gain	1.0000
14:77429000:ACTCA:A	donor_loss	1.0000
14:77429001:CTCA:C	donor_loss	1.0000
14:77429002:TCA:T	donor_loss	1.0000
14:77429003:CACAT:C	donor_loss	1.0000
14:77429004:A:AC	donor_gain	1.0000
14:77429004:AC:A	donor_loss	1.0000
14:77429005:C:A	donor_loss	1.0000
14:77429005:C:CC	donor_gain	1.0000
14:77429005:CA:C	donor_gain	1.0000
14:77429005:CAT:C	donor_gain	1.0000
14:77429005:CATCA:C	donor_gain	1.0000
14:77429092:ATAT:A	acceptor_gain	1.0000
14:77429093:TAT:T	acceptor_gain	1.0000
14:77429094:AT:A	acceptor_gain	1.0000
14:77429095:TCTGT:T	acceptor_loss	1.0000
14:77429096:C:CC	acceptor_gain	1.0000
14:77433837:CACA:C	donor_loss	1.0000

AlphaMissense

3240 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:77427627:A:G	W491R	1.000
14:77427627:A:T	W491R	1.000
14:77433894:G:T	A376D	1.000
14:77435860:C:G	R299P	1.000
14:77427625:C:A	W491C	0.999
14:77427625:C:G	W491C	0.999
14:77427626:C:G	W491S	0.999
14:77429040:G:T	A441D	0.999
14:77429718:A:T	V410D	0.999
14:77429757:C:T	G397D	0.999
14:77429764:A:G	W395R	0.999
14:77429764:A:T	W395R	0.999
14:77433874:A:G	W383R	0.999
14:77433874:A:T	W383R	0.999
14:77433888:G:T	A378D	0.999
14:77433889:C:G	A378P	0.999
14:77433891:C:G	R377P	0.999
14:77433900:A:G	L374P	0.999
14:77435279:A:C	Y343D	0.999
14:77435296:A:G	L337P	0.999
14:77435299:G:T	T336K	0.999
14:77435869:A:G	L296P	0.999
14:77442566:A:G	L243P	0.999
14:77442614:A:G	L227P	0.999
14:77443139:A:G	L204P	0.999
14:77444284:C:G	A188P	0.999
14:77444295:A:G	L184P	0.999
14:77429691:G:T	A419D	0.998
14:77429715:A:T	V411D	0.998
14:77433904:C:G	A373P	0.998

dbSNP variants (sampled 300 via entrez): RS1000172741 (14:77431578 A>T), RS1000174297 (14:77440857 T>A), RS1000401351 (14:77438199 C>A), RS1000546081 (14:77440644 C>T), RS1000711418 (14:77447858 C>A), RS1000715392 (14:77458137 G>C), RS1000740011 (14:77451120 A>C), RS1000782689 (14:77427138 C>A), RS1000914389 (14:77452239 G>A), RS1000962018 (14:77445315 T>A,G), RS1001146311 (14:77439305 A>G), RS1001346878 (14:77452506 G>C), RS1001350003 (14:77447958 G>A,C), RS1001426834 (14:77448289 A>T), RS1001580020 (14:77454734 G>A)

Disease associations

OMIM: gene MIM:613401 | disease phenotypes: MIM:613404, MIM:208085, MIM:613640

GenCC curated gene-disease

Disease	Classification	Inheritance
arthrogryposis, renal dysfunction, and cholestasis 2	Definitive	Autosomal recessive
arthrogryposis-renal dysfunction-cholestasis syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
arthrogryposis, renal dysfunction, and cholestasis 2	Definitive	AR

Mondo (4): arthrogryposis, renal dysfunction, and cholestasis 2 (MONDO:0013255), arthrogryposis-renal dysfunction-cholestasis syndrome (MONDO:0017123), arthrogryposis, renal dysfunction, and cholestasis 1 (MONDO:0008822), neuropathy, hereditary sensory and autonomic, type 1C (MONDO:0013337)

Orphanet (2): Arthrogryposis-renal dysfunction-cholestasis syndrome (Orphanet:2697), Hereditary sensory and autonomic neuropathy type 1 (Orphanet:36386)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000112	Nephropathy
HP:0000121	Nephrocalcinosis
HP:0000124	Renal tubular dysfunction
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000821	Hypothyroidism
HP:0000938	Osteopenia
HP:0000952	Jaundice
HP:0000962	Hyperkeratosis
HP:0000973	Cutis laxa
HP:0000989	Pruritus
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001339	Lissencephaly
HP:0001385	Hip dysplasia
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001531	Failure to thrive in infancy
HP:0001558	Decreased fetal movement
HP:0001562	Oligohydramnios
HP:0001629	Ventricular septal defect
HP:0001667	Right ventricular hypertrophy
HP:0001884	Talipes calcaneovalgus
HP:0001942	Metabolic acidosis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010241_237	Apolipoprotein A1 levels	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535382	Arthrogryposis renal dysfunction cholestasis syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
sodium arsenite	increases abundance, increases expression	1
jinfukang	increases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Vitamin E	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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