Is EVC2 p.Val493Ala (c.1478T>C) pathogenic?

EVC2 p.Val493Ala (c.1478T>C) is classified Likely benign in EVC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0719); Ultra-rare (popmax 0.0933%, sas); Associated with Inborn genetic diseases.

What condition is associated with EVC2 p.Val493Ala (c.1478T>C)?

EVC2 p.Val493Ala (c.1478T>C) is associated with Inborn genetic diseases, acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Val493Ala (c.1478T>C) in the general population?

EVC2 p.Val493Ala (c.1478T>C) is ultra-rare (popmax 0.0933%, sas) (gnomAD).

What do computational predictors say about EVC2 p.Val493Ala (c.1478T>C)?

AlphaMissense predicts likely benign (score 0.0719) — an in-silico prediction, not a clinical call.

EVC2 p.Val493Ala

c.1478T>C · rs202210260 · VCV767307

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0719 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0933%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0719	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -5.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.091	GERP -3.5
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	0.302	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 0.0933% South Asian · 85/91,082 alleles

Filtering AF 0.0773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0713%

Overall 0.0152% 246/1,614,066 alleles · ultra-rare exomes 234/1,461,730 · genomes 12/152,336 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0933%	1,072
Remaining individualsnot grpmax-eligible	0.0336%	2,976
Admixed American	0.0167%	6,002
European (non-Finnish)	0.0103%	9,672
African / African-American	0.00666%	15,011
Finnishnot grpmax-eligible	0.00469%	21,344

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: EVC2
Protein: p.Val493Ala
Coding: c.1478T>C
MANE Select: NM_147127
dbSNP: rs202210260
Type: single nucleotide variant
Location: chr4:5632025 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.33

Full EVC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrofacial dysostosis, Weyers type Ellis-van Creveld syndrome

Similar variants

EVC2 p.Val493Ile Uncertain significance ★ ⚠ same residue
EVC2 p.Val493Leu Uncertain significance ★ ⚠ same residue
EVC2 c.2046+1G>A Likely pathogenic ★★ same condition
EVC2 c.2047-2A>G Likely pathogenic ★★ same condition
EVC2 c.229-1G>T Likely pathogenic ★★ same condition
EVC2 c.229-2A>G Likely pathogenic ★★ same condition
EVC2 c.3360+1G>A Pathogenic ★★ same condition
EVC2 c.3659+2T>C 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/evc2-p-val493ala (accessed [today's date]).

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