Is EVC p.Ala376Val (c.1127C>T) pathogenic?

EVC p.Ala376Val (c.1127C>T) is classified Benign/Likely benign in EVC (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-03). AlphaMissense: likely benign (0.0921); Rare (popmax 0.954%, afr); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Ala376Val (c.1127C>T)?

EVC p.Ala376Val (c.1127C>T) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Ala376Val (c.1127C>T) in the general population?

EVC p.Ala376Val (c.1127C>T) is rare (popmax 0.954%, afr) (gnomAD).

What do computational predictors say about EVC p.Ala376Val (c.1127C>T)?

AlphaMissense predicts likely benign (score 0.0921) — an in-silico prediction, not a clinical call.

EVC p.Ala376Val

c.1127C>T · rs142535134 · VCV199191

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0921 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.954%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.0921	likely benign
REVEL	0.005	strongly benign-leaning
SaProt	LLR -3.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -3.7
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	2.872	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.954% African / African-American · 716/75,068 alleles

Filtering AF 0.896% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.873%

Overall 0.0495% 799/1,614,198 alleles · rare exomes 367/1,461,862 · genomes 432/152,336 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.954%	105
Admixed American	0.0583%	1,715
Remaining individualsnot grpmax-eligible	0.0512%	1,953
Middle Eastern	0.033%	3,031
South Asian	0.00329%	30,363
European (non-Finnish)	0.000932%	107,275

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EVC
Protein: p.Ala376Val
Coding: c.1127C>T
MANE Select: NM_153717
dbSNP: rs142535134
Type: single nucleotide variant
Location: chr4:5752864 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49

Full EVC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acrofacial dysostosis, Weyers type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC p.Ala376= Likely benign ★★ same residue
EVC c.1098+1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.175-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1886+1G>C Likely pathogenic ★★ same condition
EVC c.1886+5G>A Pathogenic ★★ same condition
EVC c.1886+5G>T Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/evc-p-ala376val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown