Is EVC2 p.Ser403Arg (c.1209C>A) pathogenic?

EVC2 p.Ser403Arg (c.1209C>A) is classified Uncertain significance in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-03). AlphaMissense: likely pathogenic (0.8987); Ultra-rare (popmax 0.0164%, mid); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Ser403Arg (c.1209C>A)?

EVC2 p.Ser403Arg (c.1209C>A) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Ser403Arg (c.1209C>A) in the general population?

EVC2 p.Ser403Arg (c.1209C>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about EVC2 p.Ser403Arg (c.1209C>A)?

AlphaMissense predicts likely pathogenic (score 0.8987) — an in-silico prediction, not a clinical call.

EVC2 p.Ser403Arg

c.1209C>A · rs772660326 · VCV2138881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8987 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.8987	likely pathogenic · top 2% in EVC2
REVEL	0.407	indeterminate
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.3	GERP 1.3, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	23.1	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,034 alleles · ultra-rare exomes 3/1,461,890 · genomes 1/152,144 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.000254%	393,346

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.Ser403Arg
Coding: c.1209C>A
MANE Select: NM_147127
dbSNP: rs772660326
Type: single nucleotide variant
Location: chr4:5640775 (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

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

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC2 p.Ser403Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
EVC2 p.Ser403= Likely benign ★ 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-ser403arg (accessed [today's date]).

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