Is EVC p.Arg647Gln (c.1940G>A) pathogenic?

EVC p.Arg647Gln (c.1940G>A) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-15). AlphaMissense: likely benign (0.148); Rare (popmax 0.385%, afr); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Arg647Gln (c.1940G>A)?

EVC p.Arg647Gln (c.1940G>A) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Arg647Gln (c.1940G>A) in the general population?

EVC p.Arg647Gln (c.1940G>A) is rare (popmax 0.385%, afr) (gnomAD).

What do computational predictors say about EVC p.Arg647Gln (c.1940G>A)?

AlphaMissense predicts likely benign (score 0.148) — an in-silico prediction, not a clinical call.

EVC p.Arg647Gln

c.1940G>A · rs35401386 · VCV500274

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.148 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.385%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.148	likely benign
REVEL	0.392	indeterminate
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	27.4	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 0.385% African / African-American · 289/75,070 alleles

Filtering AF 0.348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.334%

Overall 0.0266% 430/1,613,530 alleles · rare exomes 255/1,461,186 · genomes 175/152,344 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.385%	260
Admixed American	0.0566%	1,766
Remaining individualsnot grpmax-eligible	0.048%	2,083
Middle Eastern	0.033%	3,031
South Asian	0.00988%	10,120
European (non-Finnish)	0.00559%	17,879

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.Arg647Gln
Coding: c.1940G>A
MANE Select: NM_153717
dbSNP: rs35401386
Type: single nucleotide variant
Location: chr4:5797075 (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.Arg647Pro Uncertain significance ★★ ⚠ same residue
EVC p.Arg647Trp Uncertain significance ★★ ⚠ same residue
EVC p.Arg647= Likely benign ★ same residue
EVC p.Arg647_Ala650del Uncertain significance 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

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-arg647gln (accessed [today's date]).

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