ATP6V1E1

Summary

ATP6V1E1 (ATPase H+ transporting V1 subunit E1, HGNC:857) is a protein-coding gene on chromosome 22q11.21, encoding V-type proton ATPase subunit E 1 (P36543). Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. It is a common-essential gene (DepMap: required in 98.4% of cancer cell lines).

This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. This gene encodes alternate transcriptional splice variants, encoding different V1 domain E subunit isoforms. Pseudogenes for this gene have been found in the genome.

Source: NCBI Gene 529 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive cutis laxa type 2C (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 213 total
• Phenotypes (HPO): 112
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 98.4% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001696

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:857
Approved symbol	ATP6V1E1
Name	ATPase H+ transporting V1 subunit E1
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	P31, Vma4, ATP6E2
Ensembl gene	ENSG00000131100
Ensembl biotype	protein_coding
OMIM	108746
Entrez	529

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000253413, ENST00000399796, ENST00000399798, ENST00000413576, ENST00000460085, ENST00000473248, ENST00000478963, ENST00000481365, ENST00000484653, ENST00000933759, ENST00000933760, ENST00000933762, ENST00000933763

RefSeq mRNA: 3 — MANE Select: NM_001696 NM_001039366, NM_001039367, NM_001696

CCDS: CCDS13745, CCDS42977, CCDS42978

Canonical transcript exons

ENST00000253413 — 9 exons

Exon	Start	End
ENSE00000650331	17594529	17594616
ENSE00000650333	17598194	17598288
ENSE00001141765	17592136	17592736
ENSE00003503886	17600027	17600095
ENSE00003539390	17628603	17628749
ENSE00003633644	17619461	17619526
ENSE00003642837	17612812	17612878
ENSE00003646084	17601092	17601181
ENSE00003674940	17613211	17613320

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 93.3689 / max 2109.9813, expressed in 1824 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193090	78.5742	1822
193089	14.7946	1785

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.37	gold quality
prefrontal cortex	UBERON:0000451	99.34	gold quality
pons	UBERON:0000988	99.22	gold quality
right frontal lobe	UBERON:0002810	99.22	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.11	gold quality
frontal cortex	UBERON:0001870	99.07	gold quality
frontal lobe	UBERON:0016525	99.07	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.96	gold quality
cingulate cortex	UBERON:0003027	98.93	gold quality
anterior cingulate cortex	UBERON:0009835	98.90	gold quality
neocortex	UBERON:0001950	98.89	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.89	gold quality
nucleus accumbens	UBERON:0001882	98.88	gold quality
superior frontal gyrus	UBERON:0002661	98.82	gold quality
frontal pole	UBERON:0002795	98.82	gold quality
right adrenal gland cortex	UBERON:0035827	98.80	gold quality
caudate nucleus	UBERON:0001873	98.79	gold quality
right adrenal gland	UBERON:0001233	98.78	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.78	gold quality
cerebral cortex	UBERON:0000956	98.77	gold quality
amygdala	UBERON:0001876	98.75	gold quality
telencephalon	UBERON:0001893	98.75	gold quality
cerebellar cortex	UBERON:0002129	98.73	gold quality
cerebellar hemisphere	UBERON:0002245	98.73	gold quality
spinal cord	UBERON:0002240	98.71	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.70	gold quality
islet of Langerhans	UBERON:0000006	98.67	gold quality
Ammon’s horn	UBERON:0001954	98.67	gold quality
left adrenal gland	UBERON:0001234	98.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	37.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): POU2F1

miRNA regulators (miRDB)

31 targeting ATP6V1E1, 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-4533	100.00	69.48	2758
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-499A-3P	99.18	69.20	1392
HSA-MIR-499B-3P	99.18	69.27	1391
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-216B-3P	98.55	67.19	1223
HSA-MIR-1227-3P	97.36	66.94	834
HSA-MIR-1236-5P	96.62	66.38	856
HSA-MIR-6834-5P	96.25	64.88	823
HSA-MIR-4704-5P	96.13	68.67	608
HSA-MIR-7109-3P	94.23	67.19	743

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 98.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 9)

• Rat vacuolar H(+)ATPase associates with NHE-RF (Na(+)/H(+) exchanger regulatory factor); the E subunit was co-immunoprecipitated from rat kidney cytosol with NHE-RF antibodies. (PMID:10748165)
• The mouse V-ATPase E may participate in the regulation of the mSos1-dependent Rac1 signaling pathway involved in growth factor receptor-mediated cell growth control. (PMID:11560919)
• Data demonstrate the physiological significance of the interaction between the E and H subunits of V-ATPase and extend previous studies on the arrangement of subunits on the peripheral stalk of V-ATPase. (PMID:12163484)
• HuR shows increased binding to some V-ATPase mRNAs during ATP depletion; siRNA-mediated knockdown of HuR results in diminished V-ATPase expression (PMID:16155006)
• The genes CECR2, SLC25A18 and ATP6V1E1, mapping within the critical region for cat eye syndrome (CES), may be responsible for anorectal, renal and preauricular anomalies in patients with CES. (PMID:22395867)
• Low-grade PanIN lesions with typical columnar morphology displayed diffuse labeling of the V1E subunit. In advanced lesions it was found along the basolateral membranes. (PMID:25072283)
• expression of the V-ATPase V1E1 has prognostic significance in esophageal squamous cell carcinoma, and is closely linked to migration, invasion, and aerobic glycolysis in esophageal cancer cells (PMID:27384996)
• We report biallelic mutations in ATP6V1E1 and ATP6V1A, respectively encoding the E1 and A subunits of the V1 domain of V-ATPase, as a cause of distinct metabolic and multisystemic cutis laxa entities. (PMID:28065471)
• Loss of zebrafish atp6v1e1b, encoding a subunit of vacuolar ATPase, recapitulates human ARCL type 2C syndrome and identifies multiple pathobiological signatures. (PMID:34143769)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp6v1e1a	ENSDARG00000014085
danio_rerio	atp6v1e1b	ENSDARG00000030694
mus_musculus	Atp6v1e1	ENSMUSG00000019210
rattus_norvegicus	Atp6v1e1	ENSRNOG00000011905
drosophila_melanogaster	Vha26	FBGN0283535
caenorhabditis_elegans		WBGENE00006917

Paralogs (1): ATP6V1E2 (ENSG00000250565)

Protein

Protein identifiers

V-type proton ATPase subunit E 1 — P36543 (reviewed: P36543)

Alternative names: V-ATPase 31 kDa subunit, Vacuolar proton pump subunit E 1

All UniProt accessions (3): P36543, C9J8H1, Q53Y06

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment.

Subunit / interactions. V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex. The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H. The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c’’, rotary subunit d, subunits e and f, and the accessory subunits ATP6AP1/Ac45 and ATP6AP2/PRR. Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2. Interacts with ALDOC. Interacts with RAB11B.

Subcellular location. Apical cell membrane. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Clathrin-coated vesicle membrane.

Tissue specificity. Kidney; localizes to early distal nephron, encompassing thick ascending limbs and distal convoluted tubules (at protein level). Ubiquitous. High expression in the skin.

Disease relevance. Cutis laxa, autosomal recessive, 2C (ARCL2C) [MIM:617402] A form of cutis laxa, a disorder characterized by an excessive congenital skin wrinkling, a large fontanelle with delayed closure, a typical facial appearance with downslanting palpebral fissures, and a general connective tissue weakness. Most ARCL2C patients exhibit severe hypotonia as well as cardiovascular involvement. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the V-ATPase E subunit family.

Isoforms (3)

UniProt ID	Names	Canonical?
P36543-1	1	yes
P36543-2	2
P36543-3	3

RefSeq proteins (3): NP_001034455, NP_001034456, NP_001687* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002842	ATPase_V1_Esu	Family
IPR038495	ATPase_E_C	Homologous_superfamily

Pfam: PF01991

UniProt features (23 total): strand 6, helix 6, sequence variant 3, sequence conflict 2, modified residue 2, splice variant 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6WLZ	ELECTRON MICROSCOPY	2.9
6WM2	ELECTRON MICROSCOPY	3.1
6WM3	ELECTRON MICROSCOPY	3.4
9CF8	ELECTRON MICROSCOPY	3.46
9CFC	ELECTRON MICROSCOPY	3.47
6WM4	ELECTRON MICROSCOPY	3.6
7U4T	ELECTRON MICROSCOPY	3.6
7UNF	ELECTRON MICROSCOPY	4.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36543-F1	95.06	0.95

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 (2): 2, 56

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1222556	ROS and RNS production in phagocytes
R-HSA-77387	Insulin receptor recycling
R-HSA-917977	Transferrin endocytosis and recycling
R-HSA-9639288	Amino acids regulate mTORC1
R-HSA-983712	Ion channel transport
R-HSA-9857377	Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy

MSigDB gene sets: 508 (showing top): REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_AUTOPHAGY, MODY_HIPPOCAMPUS_POSTNATAL, REACTOME_INNATE_IMMUNE_SYSTEM, MORF_RAB5A, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MACROAUTOPHAGY, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN

GO Biological Process (4): regulation of macroautophagy (GO:0016241), synaptic vesicle lumen acidification (GO:0097401), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811)

GO Molecular Function (3): proton-transporting ATPase activity, rotational mechanism (GO:0046961), ATPase binding (GO:0051117), protein binding (GO:0005515)

GO Cellular Component (17): vacuolar proton-transporting V-type ATPase, V1 domain (GO:0000221), lysosomal membrane (GO:0005765), endosome (GO:0005768), cytosol (GO:0005829), microvillus (GO:0005902), apical plasma membrane (GO:0016324), proton-transporting two-sector ATPase complex (GO:0016469), clathrin-coated vesicle membrane (GO:0030665), synaptic vesicle membrane (GO:0030672), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), proton-transporting two-sector ATPase complex, catalytic domain (GO:0033178), synapse (GO:0045202), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Innate Immune System	1
Signaling by Insulin receptor	1
Iron uptake and transport	1
Cellular response to starvation	1
Transport of small molecules	1
MITF-M-dependent gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	2
membrane protein complex	2
regulation of autophagy	1
macroautophagy	1
intercellular transport	1
synaptic vesicle maturation	1
establishment of localization in cell	1
neuron cellular homeostasis	1
synaptic vesicle cycle	1
proton transmembrane transport	1
monoatomic cation transmembrane transport	1
transport	1
proton transmembrane transporter activity	1
ATPase-coupled monoatomic cation transmembrane transporter activity	1
ATPase activity, coupled to transmembrane movement of ions, rotational mechanism	1
enzyme binding	1
binding	1
vacuole	1
vacuolar proton-transporting V-type ATPase complex	1
proton-transporting V-type ATPase, V1 domain	1
lysosome	1
lytic vacuole membrane	1
endomembrane system	1
cytoplasmic vesicle	1
actin filament bundle	1
actin-based cell projection	1
apical part of cell	1
plasma membrane region	1
clathrin-coated vesicle	1
coated vesicle membrane	1
synaptic vesicle	1
exocytic vesicle membrane	1
extracellular vesicle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
intracellular vesicle	1
proton-transporting two-sector ATPase complex	1
cell junction	1

Protein interactions and networks

STRING

1934 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6V1E1	ATP6V1A	P38606	928
ATP6V1E1	ATP6V1C1	P21283	886
ATP6V1E1	ATP6V1G1	O75348	876
ATP6V1E1	ATP6V1F	Q16864	873
ATP6V1E1	ATP6V1B2	P21281	866
ATP6V1E1	ATP6V1H	Q9UI12	866
ATP6V1E1	ATP6V1B1	P15313	851
ATP6V1E1	ATP6V0A1	Q93050	847
ATP6V1E1	ATP6V1G3	Q96LB4	847
ATP6V1E1	ATP6V1G2	O95670	838
ATP6V1E1	ATP6V1D	Q9Y5K8	833
ATP6V1E1	ATP6V0D1	P12953	831
ATP6V1E1	ATP6V0C	P27449	831
ATP6V1E1	ATP6V1C2	Q8NEY4	794
ATP6V1E1	ATP6V0A2	Q9Y487	778

IntAct

52 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
SCYL1	SEC31A	psi-mi:“MI:0914”(association)	0.710
ATP6V1C2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.640
PSG9	CCDC85C	psi-mi:“MI:0914”(association)	0.530
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
ATP6AP2	ATP6V1C1	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
ATP6V0A1	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
ATP6V1A	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
ATP6V1B2	ATP6V1G1	psi-mi:“MI:0914”(association)	0.530
ATP6V0A4	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
ATP6V1G2	ATP6V1B1	psi-mi:“MI:0914”(association)	0.530
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
ATP6V1E1	MESD	psi-mi:“MI:0915”(physical association)	0.370
Rmdn3	DERL1	psi-mi:“MI:0914”(association)	0.350
Chmp4b		psi-mi:“MI:0914”(association)	0.350
CHMP4B	ELOC	psi-mi:“MI:0914”(association)	0.350
GOLT1B		psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
BCAR1	MYO1C	psi-mi:“MI:0914”(association)	0.350
ATP6V1C2	POTEF	psi-mi:“MI:0914”(association)	0.350
ATP6V1B1	ATP6V1G1	psi-mi:“MI:0914”(association)	0.350
TLDC2	ATP6V1B2	psi-mi:“MI:0914”(association)	0.350
ATP6V1A		psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350

BioGRID (201): ATP6V1E1 (Affinity Capture-RNA), ATP6V1E1 (Affinity Capture-MS), ATP6V1E1 (Affinity Capture-MS), ATP6V1E1 (Two-hybrid), ATP6V1E1 (Affinity Capture-MS), ATP1B1 (Co-fractionation), ATP6V1A (Co-fractionation), ATP6V1B2 (Co-fractionation), ATP6V1D (Co-fractionation), ATP6V1E1 (Co-fractionation), ATP6V1E1 (Co-fractionation), ATP6V1E1 (Co-fractionation), ATP6V1E1 (Co-fractionation), ATP6V1F (Co-fractionation), ATP6V1H (Co-fractionation)

ESM2 similar proteins: A1Z3X3, A4GWN3, A5PK00, B2RYZ5, B9SQI7, E9Q4Z2, O00763, O23948, O82703, O88447, P0C0A2, P0CAN7, P11019, P31402, P36543, P50518, P54611, Q04499, Q32LB7, Q39258, Q3KPT5, Q3U4G0, Q40272, Q41396, Q4A1L3, Q4R761, Q5E9S8, Q5RJU0, Q5RK19, Q5U3V9, Q6DDF4, Q6GP52, Q6PCU2, Q7SZ78, Q7ZVK4, Q86VN1, Q8VZM1, Q91XD6, Q95X44, Q96A05

Diamond homologs: O00780, O13687, O23948, O94072, P0CAN7, P11019, P22203, P31402, P36543, P50518, P54611, Q01278, Q32LB7, Q39258, Q40272, Q41396, Q4R761, Q6PCU2, Q95X44, Q96A05, Q9C9Z8, Q9D593, Q9MB46, Q9SWE7, Q9U1G5, O27039, Q3J9F2, O06501, Q5JDS0, Q9UXU4, A6UT32, C6A5F1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 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
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	10	139.9×	9e-19
Insulin receptor recycling	14	111.0×	3e-24
Transferrin endocytosis and recycling	14	107.5×	3e-24
ROS and RNS production in phagocytes	14	98.0×	9e-24
Amino acids regulate mTORC1	11	45.9×	2e-14
Ion channel transport	14	28.0×	2e-15

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	12	204.3×	3e-24
vacuolar acidification	11	146.5×	3e-20
lysosomal lumen acidification	6	73.5×	7e-09
proton transmembrane transport	12	68.1×	1e-17
regulation of macroautophagy	12	64.5×	2e-17

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	91
Benign	46

Top pathogenic / likely-pathogenic (0)

SpliceAI

1072 predictions. Top by Δscore:

Variant	Effect	Δscore
22:17592733:TCAT:T	acceptor_gain	1.0000
22:17592734:CAT:C	acceptor_gain	1.0000
22:17592734:CATC:C	acceptor_gain	1.0000
22:17592735:AT:A	acceptor_gain	1.0000
22:17592736:TC:T	acceptor_loss	1.0000
22:17592737:C:CC	acceptor_gain	1.0000
22:17594525:TCACC:T	donor_loss	1.0000
22:17594527:A:AC	donor_gain	1.0000
22:17594527:AC:A	donor_gain	1.0000
22:17594527:ACC:A	donor_loss	1.0000
22:17594528:C:CT	donor_gain	1.0000
22:17594528:CC:C	donor_gain	1.0000
22:17594528:CCTG:C	donor_gain	1.0000
22:17594612:CAGCT:C	acceptor_gain	1.0000
22:17594613:AGCT:A	acceptor_gain	1.0000
22:17594614:GCTC:G	acceptor_loss	1.0000
22:17594615:CT:C	acceptor_gain	1.0000
22:17594617:C:CC	acceptor_gain	1.0000
22:17594618:T:G	acceptor_loss	1.0000
22:17594620:C:CT	acceptor_gain	1.0000
22:17594621:A:T	acceptor_gain	1.0000
22:17598192:A:AC	donor_gain	1.0000
22:17598193:C:CC	donor_gain	1.0000
22:17598193:CATGT:C	donor_gain	1.0000
22:17598288:CCTG:C	acceptor_loss	1.0000
22:17598289:C:CC	acceptor_gain	1.0000
22:17598289:CT:C	acceptor_loss	1.0000
22:17598290:T:A	acceptor_loss	1.0000
22:17600021:CTTTA:C	donor_loss	1.0000
22:17600024:TACC:T	donor_loss	1.0000

AlphaMissense

1510 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:17592690:C:A	R222M	1.000
22:17612837:A:G	L84P	1.000
22:17612853:C:G	A79P	1.000
22:17613286:A:G	L45P	1.000
22:17613294:T:A	K42N	1.000
22:17613294:T:G	K42N	1.000
22:17613306:G:C	F38L	1.000
22:17613306:G:T	F38L	1.000
22:17613308:A:G	F38L	1.000
22:17613320:C:G	A34P	1.000
22:17619466:C:G	A32P	1.000
22:17619481:C:G	A27P	1.000
22:17619482:T:A	K26N	1.000
22:17619482:T:G	K26N	1.000
22:17619493:C:G	A23P	1.000
22:17619498:T:G	Q21P	1.000
22:17619504:A:T	I19N	1.000
22:17619506:G:C	F18L	1.000
22:17619506:G:T	F18L	1.000
22:17619507:A:C	F18C	1.000
22:17619507:A:G	F18S	1.000
22:17619508:A:G	F18L	1.000
22:17619508:A:T	F18I	1.000
22:17619511:C:G	A17P	1.000
22:17619515:C:A	M15I	1.000
22:17619515:C:G	M15I	1.000
22:17619515:C:T	M15I	1.000
22:17619516:A:G	M15T	1.000
22:17592683:A:C	F224L	0.999
22:17592683:A:T	F224L	0.999

dbSNP variants (sampled 300 via entrez): RS1000000943 (22:17611940 C>A,G), RS1000000965 (22:17630228 A>AC), RS1000022629 (22:17597589 G>A), RS1000030376 (22:17612270 A>G), RS1000162293 (22:17620141 C>G,T), RS1000280981 (22:17606493 A>C), RS1000315135 (22:17625071 T>TA), RS1000443614 (22:17620329 A>G), RS1000500950 (22:17618509 T>A,C,G), RS1000582171 (22:17625240 C>G,T), RS1000691607 (22:17595048 G>A), RS1000920470 (22:17623455 G>A), RS1000989098 (22:17614659 C>A,T), RS1000993831 (22:17596113 G>A,C), RS1001013275 (22:17623069 T>A,G)

Disease associations

OMIM: gene MIM:108746 | disease phenotypes: MIM:617402

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive cutis laxa type 2C	Strong	Autosomal recessive
autosomal recessive cutis laxa type 2, classic type	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal recessive cutis laxa type 2C	Limited	AR

Mondo (3): autosomal recessive cutis laxa type 2C (MONDO:0027462), cutis laxa (MONDO:0016175), autosomal recessive cutis laxa type 2, classic type (MONDO:0009054)

Orphanet (1): Cutis laxa (Orphanet:209)

HPO phenotypes

112 total (30 of 112 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000121	Nephrocalcinosis
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000253	Progressive microcephaly
HP:0000272	Malar flattening
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000325	Triangular face
HP:0000327	Hypoplasia of the maxilla
HP:0000343	Long philtrum
HP:0000350	Small forehead
HP:0000369	Low-set ears
HP:0000444	Convex nasal ridge
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000581	Blepharophimosis
HP:0000621	Entropion
HP:0000629	Periorbital fullness
HP:0000639	Nystagmus
HP:0000670	Carious teeth
HP:0000678	Dental crowding
HP:0000726	Dementia

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003483	Cutis Laxa	C16.320.850.180; C17.300.230; C17.800.827.180
C562632	Cutis Laxa, Autosomal Recessive, Type IIA (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066911 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — V-type ATPase

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.71	Kd	194.9	nM	CHEMBL5653589
6.71	ED50	194.9	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147924: Binding affinity to human ATP6V1E1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1949	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, increases abundance	4
bisphenol A	affects expression, decreases expression	3
Arsenic	affects cotreatment, increases abundance, increases expression, affects methylation	2
Tobacco Smoke Pollution	affects expression, increases expression	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
arsenite	affects binding, increases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
tanshinone	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
bisphenol B	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases expression, increases response to substance	1
Doxorubicin	increases expression	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Glycochenodeoxycholic Acid	decreases expression	1
Isoniazid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650966	Binding	Binding affinity to human ATP6V1E1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03887208	PHASE1/PHASE2	COMPLETED	Therapy of Scars and Cutis Laxa With Autologous Adipose Derived Mesenchymal Stem Cells
NCT01293864	Not specified	TERMINATED	Structural Analysis of Human Tissue
NCT01658163	Not specified	COMPLETED	Use of 2-octyl-cyanoacrylate Together With a Self-adhering Mesh
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07614997	Not specified	NOT_YET_RECRUITING	Effectiveness and Safety of the Ulthera® System for Skin Laxity in the Lower Face, Submentum and Neck