EVC2

Summary

EVC2 (EvC ciliary complex subunit 2, HGNC:19747) is a protein-coding gene on chromosome 4p16.2, encoding Limbin (Q86UK5). Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling.

This gene encodes a protein that functions in bone formation and skeletal development. Mutations in this gene, as well as in a neighboring gene that lies in a head-to-head configuration, cause Ellis-van Creveld syndrome, an autosomal recessive skeletal dysplasia that is also known as chondroectodermal dysplasia. Mutations in this gene also cause acrofacial dysostosis Weyers type, also referred to as Curry-Hall syndrome, a disease that combines limb and facial abnormalities. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 132884 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acrofacial dysostosis, Weyers type (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 2,282 total — 192 pathogenic, 132 likely-pathogenic
• Phenotypes (HPO): 87
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_147127

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19747
Approved symbol	EVC2
Name	EvC ciliary complex subunit 2
Location	4p16.2
Locus type	gene with protein product
Status	Approved
Aliases	LBN
Ensembl gene	ENSG00000173040
Ensembl biotype	protein_coding
OMIM	607261
Entrez	132884

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 nonsense_mediated_decay

ENST00000310917, ENST00000344408, ENST00000475313, ENST00000509670, ENST00000861567, ENST00000861568, ENST00000861569, ENST00000917734, ENST00000917735, ENST00000956873, ENST00000956874

RefSeq mRNA: 2 — MANE Select: NM_147127 NM_001166136, NM_147127

CCDS: CCDS3382, CCDS54718

Canonical transcript exons

ENST00000344408 — 22 exons

Exon	Start	End
ENSE00001287947	5640514	5640838
ENSE00001287952	5663107	5663246
ENSE00001287961	5665515	5665649
ENSE00001287970	5681260	5681313
ENSE00001287975	5685370	5685479
ENSE00001287983	5689157	5689343
ENSE00001287988	5691265	5691333
ENSE00001287993	5694335	5694501
ENSE00001422282	5708286	5708559
ENSE00001917639	5562439	5563115
ENSE00003460462	5565258	5565359
ENSE00003496436	5697593	5697647
ENSE00003522069	5618478	5618682
ENSE00003532449	5574685	5574772
ENSE00003562481	5628559	5628734
ENSE00003572362	5631793	5632032
ENSE00003573313	5576240	5576454
ENSE00003580069	5584623	5584850
ENSE00003583828	5625749	5625908
ENSE00003591518	5615422	5615544
ENSE00003603118	5622537	5622991
ENSE00003613142	5568444	5568640

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 81.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.7065 / max 101.4185, expressed in 1275 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51217	4.7065	1275

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	81.36	silver quality
calcaneal tendon	UBERON:0003701	80.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.35	gold quality
sural nerve	UBERON:0015488	80.05	gold quality
mucosa of stomach	UBERON:0001199	78.88	gold quality
stromal cell of endometrium	CL:0002255	78.53	gold quality
ventricular zone	UBERON:0003053	77.67	gold quality
left ovary	UBERON:0002119	77.30	gold quality
right ovary	UBERON:0002118	76.93	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.60	gold quality
popliteal artery	UBERON:0002250	75.09	gold quality
tibial artery	UBERON:0007610	75.08	gold quality
ascending aorta	UBERON:0001496	74.93	gold quality
aorta	UBERON:0000947	74.92	gold quality
thoracic aorta	UBERON:0001515	74.91	gold quality
endocervix	UBERON:0000458	74.69	gold quality
descending thoracic aorta	UBERON:0002345	74.41	gold quality
body of uterus	UBERON:0009853	74.36	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	73.75	gold quality
tendon	UBERON:0000043	73.67	gold quality
ectocervix	UBERON:0012249	73.56	gold quality
lower esophagus muscularis layer	UBERON:0035833	73.50	gold quality
lower esophagus	UBERON:0013473	73.45	gold quality
ovary	UBERON:0000992	73.27	gold quality
left coronary artery	UBERON:0001626	72.75	gold quality
left uterine tube	UBERON:0001303	72.38	gold quality
right coronary artery	UBERON:0001625	72.34	gold quality
tibial nerve	UBERON:0001323	72.20	gold quality
coronary artery	UBERON:0001621	71.76	gold quality
uterine cervix	UBERON:0000002	71.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.33

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting EVC2, 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-6873-3P	100.00	71.42	2626
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-2054	99.20	68.89	1699

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 23)

• EVC2 is mutated in an Ashkenazi individual with Ellis-van Creveld syndrome (PMID:12468274)
• Mutations in this gene cause Ellis-van Creveld syndrome. (PMID:12571802)
• Data provide conclusive evidence that Weyers acrofacial dysostosis and EvC syndrome are allelic and genetically heterogeneous conditions. (PMID:16404586)
• In a consanguineous pedigree diagnosed with EvC and borderline intelligence, a 520-kb homozygous deletion comprising EVC, EVC2, C4orf6, and STK32B, caused by recombination between LINE-1 elements, was detected (PMID:18454448)
• EVC and LBN play roles in cardiovascular development and disease. (PMID:19251731)
• The expression of a Weyer variant, but not the expression of a truncated protein that mimics an Ellis-van Creveld syndrome mutation, impairs Hedgehog signal transduction in NIH 3T3 cells in keeping with its dominant effect. (PMID:19810119)
• STK32b, EVC and EVC2 genes yielded suggestive evidence for linkage and disepuilibrium among cleft palate trios. (PMID:20087401)
• A novel splice site mutation (c.2047-1G>T) in intron 13 of EVC2 gene was found in a family with child diagnosed with Ellis-van Creveld syndrome in the United Arab Emirates. (PMID:20184732)
• Molecular analysis of the EVC and EVC2 genes is helpful in genetic counseling in cases with prenatally detected postaxial polydactyly, thoracic narrowness, short limbs and endocardial cushion defects. (PMID:21199751)
• Emerging molecular and developmental studies suggest that EVC and EVC2 proteins may be important for cilia function, which is implicated in the pathogenesis of heterotaxy syndromes. (PMID:21533779)
• In this study, two novel heterozygous EVC2 mutations, IVS 5-2A > G and c.2653C > T (Arg88 5X), were identified in the patient; the IVS5-2A > G mutation was inherited from the patient’s mother and the c.2653C > T from her father (PMID:21815252)
• Identification of a novel genotype in EvC will provide clues to phenotype-genotype relations and may assist not only in the clinical diagnosis of EvC but also in the interpretation of genetic information used for prenatal diagnosis and genetic counseling (PMID:23026208)
• Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes-C5orf42, EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis (PMID:23169490)
• we identified 2 independent mutations in EVC2 gene in patients with WAD, including one novel. (PMID:23220543)
• sequence analysis identified a novel nonsense mutation (p.Trp234*) in exon 8 of the EVC2 gene and 15 bp duplication in exon 14 of the EVC gene in the two families.. (PMID:26580685)
• Sequencing of both EVC and EVC2 identified two novel heterozygous splice site mutations c.384+5G>C in intron 3 and c.1465-1G>A in intron 10 in EVC, which were inherited from mother and father, respectively. (PMID:26621368)
• we detected two novel nonsense mutations and a partial deletion of EVC/EVC2 in two Vietnamese families with EvC. Moreover, we found in one family a missense mutation of EFCAB7, a possible modifier gene in EvC and its related disorders. (PMID:26748586)
• he whole exome sequencing (WES) in this family revealed two homozygous variants in EVC2 (c.30dupC; p.Thr11Hisfs*45) and TMC1 (c.1696-1G>A) genes. In family B, WES revealed novel compound heterozygous variants (p.Ser307Pro, c.2894+3A>G) in the EVC gene. (PMID:29321360)
• Novel mutation in EFCAB7 alters expression and interaction with EVC2 protein. (PMID:29845660)
• Novel Wnt10A mutations (c.521T>C and c.653T>G) and EVC2 mutation (c.1472C>T) were identified in families with selective tooth agenesis. The Wnt10A c.521T>C mutation and the EVC2 c.1472C>T mutation were considered as pathogenic for affecting highly conserved amino acids, co-segregated with phenotype and predicted to be disease-causing by SIFT and PolyPhen2. (PMID:30417976)
• Human-chimpanzee fused cells reveal cis-regulatory divergence underlying skeletal evolution. (PMID:33731941)
• Dental Anomalies in Ciliopathies: Lessons from Patients with BBS2, BBS7, and EVC2 Mutations. (PMID:36672825)
• Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis-van Creveld Syndrome. (PMID:37107645)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Evc2	ENSMUSG00000050248
rattus_norvegicus	Evc2	ENSRNOG00000007025

Paralogs (1): EVC (ENSG00000072840)

Protein

Protein identifiers

Limbin — Q86UK5 (reviewed: Q86UK5)

Alternative names: Ellis-van Creveld syndrome protein 2

All UniProt accessions (3): Q86UK5, A0A0C4DGE7, E9PFT2

UniProt curated annotations — full annotation on UniProt →

Function. Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling. Plays a critical role in bone formation and skeletal development. May be involved in early embryonic morphogenesis.

Subunit / interactions. Component of the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC; built from two subcomplexes, EVC2:EVC and EFCAB7:IQCE. Interacts with EVC. Interacts (via N-terminal end) with EFCAB7. Interacts (via N-terminal end) with IQCE.

Subcellular location. Cell membrane. Cytoplasm. Cytoskeleton. Cilium basal body. Cell projection. Cilium. Cilium membrane. Nucleus.

Tissue specificity. Found in the heart, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Disease relevance. Ellis-van Creveld syndrome (EVC) [MIM:225500] An autosomal recessive condition characterized by the clinical tetrad of chondrodystrophy, polydactyly, ectodermal dysplasia and cardiac anomalies. Patients manifest short-limb dwarfism, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital heart defects, most commonly an atrioventricular septal defect, are observed in 60% of affected individuals. The disease is caused by variants affecting the gene represented in this entry. Acrofacial dysostosis, Weyers type (WAD) [MIM:193530] An autosomal dominant condition characterized by dysplastic nails, postaxial polydactyly, dental anomalies, short limbs, short stature and normal intelligence. The phenotype is milder than Ellis-van Creveld syndrome. The disease is caused by variants affecting the gene represented in this entry.

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?
Q86UK5-1	1	yes
Q86UK5-2	2
Q86UK5-3	3

RefSeq proteins (2): NP_001159608, NP_667338* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022076	Limbin	Family
IPR026501	Limbin/EVC	Family

Pfam: PF12297

UniProt features (21 total): sequence variant 6, coiled-coil region 3, splice variant 2, topological domain 2, region of interest 2, signal peptide 1, chain 1, compositionally biased region 1, glycosylation site 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UK5-F1	73.33	0.35

Functional residue map

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

Glycosylation sites (1): 220

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-5635838	Activation of SMO
R-HSA-162582	Signal Transduction
R-HSA-5358351	Signaling by Hedgehog

MSigDB gene sets: 262 (showing top): AREB6_01, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, chr4p16, AACTTT_UNKNOWN, GOBP_SMOOTHENED_SIGNALING_PATHWAY, CUI_TCF21_TARGETS_2_UP, GOCC_CELL_PROJECTION_MEMBRANE, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOCC_PLASMA_MEMBRANE_REGION, GOCC_CILIARY_MEMBRANE, GOCC_CILIUM, GOCC_PLASMA_MEMBRANE_PROTEIN_COMPLEX, SCGGAAGY_ELK1_02, BOCHKIS_FOXA2_TARGETS, PURBEY_TARGETS_OF_CTBP1_NOT_SATB1_UP

GO Biological Process (1): smoothened signaling pathway (GO:0007224)

GO Molecular Function (0):

GO Cellular Component (9): nucleus (GO:0005634), cilium (GO:0005929), ciliary membrane (GO:0060170), plasma membrane protein complex (GO:0098797), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by Hedgehog	1
Hedgehog ‘on’ state	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell surface receptor signaling pathway	1
intracellular membrane-bounded organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cilium	1
cell projection membrane	1
bounding membrane of organelle	1
plasma membrane	1
membrane protein complex	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

818 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EVC2	EVC	P57679	986
EVC2	EFCAB7	A8K855	805
EVC2	SMO	Q99835	802
EVC2	IQCE	Q6IPM2	778
EVC2	STK32B	Q9NY57	752
EVC2	NSG1	P42857	749
EVC2	CRMP1	Q14194	736
EVC2	STX18	Q9P2W9	701
EVC2	WDR35	Q9P2L0	677
EVC2	SUFU	Q9UMX1	672
EVC2	DYNC2LI1	Q8TCX1	627
EVC2	MSX1	P28360	622
EVC2	WDR19	Q8NEZ3	611
EVC2	IFT80	Q9P2H3	600
EVC2	DYNC2I1	Q8WVS4	598

IntAct

4 interactions, top by confidence:

A	B	Type	Score
EVC2	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
EVC2	SLC33A1	psi-mi:“MI:2364”(proximity)	0.270
EVC2	PGRMC2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (91): ACBD3 (Proximity Label-MS), ACSL3 (Proximity Label-MS), AHCY (Proximity Label-MS), ALDH3A2 (Proximity Label-MS), ANKLE2 (Proximity Label-MS), ATP6AP1 (Proximity Label-MS), ATP6AP2 (Proximity Label-MS), BAG2 (Proximity Label-MS), BCAP31 (Proximity Label-MS), THEM6 (Proximity Label-MS), CAMLG (Proximity Label-MS), CCDC47 (Proximity Label-MS), CDKAL1 (Proximity Label-MS), CKAP4 (Proximity Label-MS), DDRGK1 (Proximity Label-MS)

ESM2 similar proteins: A1A5D9, A6NGB0, A9QT41, B8JK76, F6XLV1, O94927, P0C7N4, P58660, Q0KK56, Q0VG85, Q1RMI8, Q29RS0, Q2KJ21, Q2NL23, Q2TAC2, Q3LUD3, Q3V0F0, Q4QRL3, Q571B6, Q5D525, Q5ND29, Q5RD60, Q5XHZ2, Q66HR5, Q6NSJ2, Q6PHN1, Q6QZQ4, Q86UK5, Q8BFT2, Q8BP01, Q8CB62, Q8CGU1, Q8CHW5, Q8CJ40, Q8HZ57, Q8HZ58, Q8HZ59, Q8HZ60, Q8K1G2, Q8K2I2

Diamond homologs: Q86UK5, Q8K1G2, Q8MI28

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

2282 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	192
Likely pathogenic	132
Uncertain significance	630
Likely benign	1047
Benign	127

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1007423	NM_147127.5(EVC2):c.3751G>T (p.Glu1251Ter)	Pathogenic
102430	NM_147127.5(EVC2):c.3797T>G (p.Leu1266Ter)	Pathogenic
102431	NM_147127.5(EVC2):c.3797T>A (p.Leu1266Ter)	Pathogenic
102432	NM_147127.5(EVC2):c.3805G>T (p.Gly1269Ter)	Pathogenic
1070195	NM_147127.5(EVC2):c.903del (p.Phe302fs)	Pathogenic
1071133	NM_147127.5(EVC2):c.2897C>A (p.Ser966Ter)	Pathogenic
1073309	NC_000004.11:g.(?5642221)(5642585_?)del	Pathogenic
1073515	NM_147127.5(EVC2):c.1108del (p.Ser370fs)	Pathogenic
1074626	NM_147127.5(EVC2):c.1483_1484dup (p.Ser496fs)	Pathogenic
1076001	NM_147127.5(EVC2):c.1410C>G (p.Tyr470Ter)	Pathogenic
1076026	NM_147127.5(EVC2):c.1755dup (p.Tyr586fs)	Pathogenic
1076027	NM_147127.5(EVC2):c.104C>G (p.Ser35Ter)	Pathogenic
1076398	NM_147127.5(EVC2):c.253A>T (p.Lys85Ter)	Pathogenic
1076943	NM_147127.5(EVC2):c.2796_2797del (p.Cys932_Glu933delinsTer)	Pathogenic
1164043	NM_147127.5(EVC2):c.24del (p.Arg9fs)	Pathogenic
1252025	NM_147127.5(EVC2):c.2017_2021del (p.Thr673fs)	Pathogenic
1322840	NM_147127.5(EVC2):c.3091C>T (p.Gln1031Ter)	Pathogenic
1355691	NM_147127.5(EVC2):c.2954del (p.Tyr985fs)	Pathogenic
1367031	NM_147127.5(EVC2):c.3057+1del	Pathogenic
1372870	NM_147127.5(EVC2):c.3648_3649delinsTT (p.Lys1216_Arg1217delinsAsnTer)	Pathogenic
1376270	NM_147127.5(EVC2):c.1991dup (p.Lys665fs)	Pathogenic
1380831	NM_147127.5(EVC2):c.655G>T (p.Gly219Ter)	Pathogenic
1386123	NM_147127.5(EVC2):c.3655C>T (p.Gln1219Ter)	Pathogenic
1389385	NM_147127.5(EVC2):c.3487_3488dup (p.Glu1164fs)	Pathogenic
1390305	NM_147127.5(EVC2):c.2010del (p.Lys670fs)	Pathogenic
1393504	NM_147127.5(EVC2):c.2729C>G (p.Ser910Ter)	Pathogenic
1400047	NM_147127.5(EVC2):c.3523_3527dup (p.Gln1179fs)	Pathogenic
1416340	NM_147127.5(EVC2):c.3194del (p.Asp1065fs)	Pathogenic
1423173	NM_147127.5(EVC2):c.1857_1866del (p.Gln619fs)	Pathogenic
1428691	NM_147127.5(EVC2):c.832A>T (p.Lys278Ter)	Pathogenic

SpliceAI

4664 predictions. Top by Δscore:

Variant	Effect	Δscore
4:5568439:CTCA:C	donor_loss	1.0000
4:5568440:TCA:T	donor_loss	1.0000
4:5568441:CACC:C	donor_loss	1.0000
4:5568442:A:AC	donor_gain	1.0000
4:5568442:A:C	donor_loss	1.0000
4:5568442:ACCT:A	donor_gain	1.0000
4:5568443:C:CC	donor_gain	1.0000
4:5568443:CCT:C	donor_gain	1.0000
4:5568443:CCTC:C	donor_gain	1.0000
4:5568637:GCTC:G	acceptor_gain	1.0000
4:5568638:CTC:C	acceptor_gain	1.0000
4:5568638:CTCC:C	acceptor_gain	1.0000
4:5568639:TC:T	acceptor_gain	1.0000
4:5568639:TCC:T	acceptor_loss	1.0000
4:5568639:TCCT:T	acceptor_gain	1.0000
4:5568640:CC:C	acceptor_gain	1.0000
4:5568641:C:CA	acceptor_loss	1.0000
4:5568641:C:CC	acceptor_gain	1.0000
4:5568642:T:C	acceptor_loss	1.0000
4:5574768:TCAAA:T	acceptor_gain	1.0000
4:5574769:CAAA:C	acceptor_gain	1.0000
4:5574769:CAAAC:C	acceptor_gain	1.0000
4:5574771:AA:A	acceptor_gain	1.0000
4:5574773:C:CC	acceptor_gain	1.0000
4:5574778:G:GC	acceptor_gain	1.0000
4:5576325:C:A	donor_gain	1.0000
4:5576364:A:AC	donor_gain	1.0000
4:5576365:C:CC	donor_gain	1.0000
4:5584618:CTCA:C	donor_loss	1.0000
4:5584619:TCA:T	donor_loss	1.0000

AlphaMissense

8541 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:5685398:G:T	A263D	0.987
4:5689243:T:A	D207V	0.986
4:5689243:T:G	D207A	0.986
4:5689244:C:G	D207H	0.985
4:5691274:T:A	K170N	0.985
4:5691274:T:G	K170N	0.985
4:5689176:A:C	F229L	0.984
4:5689176:A:T	F229L	0.984
4:5689178:A:G	F229L	0.984
4:5685392:A:G	L265P	0.982
4:5685392:A:T	L265H	0.980
4:5689303:A:G	L187P	0.980
4:5640638:C:G	R449P	0.979
4:5640618:C:G	A456P	0.978
4:5685385:A:C	F267L	0.977
4:5685385:A:T	F267L	0.977
4:5685387:A:G	F267L	0.977
4:5691275:T:A	K170I	0.977
4:5691276:T:C	K170E	0.977
4:5691281:A:G	F168S	0.976
4:5689244:C:A	D207Y	0.975
4:5691276:T:G	K170Q	0.975
4:5685449:G:T	A246D	0.974
4:5689297:A:T	V189D	0.969
4:5640788:C:G	R399P	0.967
4:5689242:G:C	D207E	0.966
4:5689242:G:T	D207E	0.966
4:5628669:A:C	F592L	0.964
4:5628669:A:T	F592L	0.964
4:5628671:A:G	F592L	0.964

dbSNP variants (sampled 300 via entrez): RS1000012241 (4:5570039 A>C,G), RS1000023932 (4:5662060 G>A), RS10000314 (4:5709368 G>A,C,T), RS1000049419 (4:5535057 A>G), RS1000054368 (4:5650991 G>A), RS1000056600 (4:5661695 T>C), RS1000060661 (4:5546091 C>G,T), RS1000065743 (4:5696067 A>G), RS1000070219 (4:5593333 C>T), RS1000089560 (4:5665671 A>G), RS1000108501 (4:5540685 A>G), RS1000112515 (4:5557081 G>A), RS1000123852 (4:5627997 A>G), RS1000137499 (4:5539480 AACTT>A), RS10001382 (4:5612280 C>T)

Disease associations

OMIM: gene MIM:607261 | disease phenotypes: MIM:193530, MIM:225500, MIM:249000, MIM:208500, MIM:602639, MIM:269860, MIM:263520

GenCC curated gene-disease

Disease	Classification	Inheritance
acrofacial dysostosis, Weyers type	Definitive	Autosomal recessive
Ellis-van Creveld syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
acrofacial dysostosis, Weyers type	Definitive	AD
Ellis-van Creveld syndrome	Definitive	AR

Mondo (7): acrofacial dysostosis, Weyers type (MONDO:0008673), Ellis-van Creveld syndrome (MONDO:0009162), Meckel syndrome (MONDO:0018921), Jeune syndrome (MONDO:0018770), tooth agenesis, selective, 2 (MONDO:0011265), Beemer-Langer syndrome (MONDO:0010024), short-rib thoracic dysplasia 6 with or without polydactyly (MONDO:0009894)

Orphanet (5): Ellis Van Creveld syndrome (Orphanet:289), Acrofacial dysostosis, Weyers type (Orphanet:952), Meckel syndrome (Orphanet:564), Jeune syndrome (Orphanet:474), Short rib-polydactyly syndrome, Beemer-Langer type (Orphanet:93268)

HPO phenotypes

87 total (30 of 87 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000028	Cryptorchidism
HP:0000039	Epispadias
HP:0000047	Hypospadias
HP:0000069	Abnormality of the ureter
HP:0000072	Hydroureter
HP:0000077	Abnormality of the kidney
HP:0000164	Abnormality of the dentition
HP:0000190	Abnormal oral frenulum morphology
HP:0000204	Cleft upper lip
HP:0000233	Thin vermilion border
HP:0000395	Prominent antihelix
HP:0000486	Strabismus
HP:0000601	Hypotelorism
HP:0000668	Hypodontia
HP:0000684	Delayed eruption of teeth
HP:0000691	Microdontia
HP:0000695	Natal tooth
HP:0000698	Conical tooth
HP:0000768	Pectus carinatum
HP:0000773	Short ribs
HP:0000774	Narrow chest
HP:0000888	Horizontal ribs
HP:0000924	Abnormality of the skeletal system
HP:0000968	Ectodermal dysplasia
HP:0001156	Brachydactyly
HP:0001161	Hand polydactyly
HP:0001162	Postaxial hand polydactyly

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004100_3	Body mass index (change over time) in gastrointestinal cancer or chronic obstructive pulmonary disease	1.000000e-06
GCST008551_12	Simvastatin-induced myopathy	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005937	longitudinal BMI measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004613	Ellis-Van Creveld Syndrome	C05.116.099.708.327; C16.131.077.350.398; C16.131.831.350.398; C16.320.850.250.398; C17.800.804.350.398; C17.800.827.250.398
C537571	Jeune syndrome (supp.)
C537599	Short rib-polydactyly syndrome, Beemer type (supp.)
C566513	Tooth Agenesis, Selective, 2 (supp.)
C536695	Weyers acrofacial dysostosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases mutagenesis	4
sodium arsenite	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	decreases methylation	1
mercuric bromide	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Endosulfan	increases expression	1
Estradiol	affects expression	1
Methyl Methanesulfonate	increases expression	1
Phthalic Acids	increases methylation	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases expression	1
Aflatoxin B1	increases methylation	1
Acrylamide	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02157038	Not specified	COMPLETED	Neuromuscular Mechanisms Underlying Poor Recovery From Whiplash Injuries
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT00948376	Not specified	COMPLETED	Natural History of Asphyxiating Thoracic Dystrophy (DTJ)
NCT04143841	Not specified	TERMINATED	Viveye Ocular Magnetic Neurostimulation System (OMNS) for the Management of Severe Dry Eye Disease
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)