Is EVC p.Arg438Gln (c.1313G>A) pathogenic?

EVC p.Arg438Gln (c.1313G>A) is classified Benign/Likely benign in EVC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-16). AlphaMissense: likely benign (0.0823); Rare (popmax 0.659%, sas); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Arg438Gln (c.1313G>A)?

EVC p.Arg438Gln (c.1313G>A) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Arg438Gln (c.1313G>A) in the general population?

EVC p.Arg438Gln (c.1313G>A) is rare (popmax 0.659%, sas) (gnomAD).

What do computational predictors say about EVC p.Arg438Gln (c.1313G>A)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

EVC p.Arg438Gln

c.1313G>A · rs373718642 · VCV349174

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.659%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -5.60	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 2.7	GERP -0.067, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	21.3	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 0.659% South Asian · 582/88,262 alleles

Filtering AF 0.615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.597%

Overall 0.0428% 680/1,588,120 alleles · rare exomes 648/1,435,768 · genomes 32/152,352 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.659%	152
Middle Eastern	0.0764%	1,309
Remaining individualsnot grpmax-eligible	0.0406%	2,460
Admixed American	0.0109%	9,153
European (non-Finnish)	0.00522%	19,152
East Asian	0.00228%	43,806
African / African-American	0.00134%	74,754

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.Arg438Gln
Coding: c.1313G>A
MANE Select: NM_153717
dbSNP: rs373718642
Type: single nucleotide variant
Location: chr4:5753050 (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.Arg438Trp Uncertain significance ★★ ⚠ same residue
EVC p.Arg438= Likely benign ★ same residue
EVC p.Arg438fs Pathogenic ★ 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

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-arg438gln (accessed [today's date]).

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