Is EVC p.Val441Ile (c.1321G>A) pathogenic?

EVC p.Val441Ile (c.1321G>A) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0849); Ultra-rare (popmax 0.0533%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EVC p.Val441Ile (c.1321G>A)?

EVC p.Val441Ile (c.1321G>A) is associated with Inborn genetic diseases, acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Val441Ile (c.1321G>A) in the general population?

EVC p.Val441Ile (c.1321G>A) is ultra-rare (popmax 0.0533%, nfe) (gnomAD).

What do computational predictors say about EVC p.Val441Ile (c.1321G>A)?

AlphaMissense predicts likely benign (score 0.0849) — an in-silico prediction, not a clinical call.

EVC p.Val441Ile

c.1321G>A · rs202150959 · VCV664480

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0849 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0849	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.75	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 1.9	GERP 0.12, phastCons 0.017
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	9.171	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 0.0533% European (non-Finnish) · 629/1,179,992 alleles

Filtering AF 0.0498% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0484%

Overall 0.0433% 699/1,614,108 alleles · ultra-rare exomes 648/1,461,814 · genomes 51/152,294 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0533%	1,876
Admixed American	0.04%	2,501
Finnishnot grpmax-eligible	0.0344%	2,909
Middle Eastern	0.033%	3,028
Remaining individualsnot grpmax-eligible	0.0224%	4,465
African / African-American	0.00666%	15,012
South Asian	0.00329%	30,359

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.Val441Ile
Coding: c.1321G>A
MANE Select: NM_153717
dbSNP: rs202150959
Type: single nucleotide variant
Location: chr4:5753790 (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

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

EVC p.Val441= 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-val441ile (accessed [today's date]).

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