Is EVC2 p.Trp337Arg (c.1009T>A) pathogenic?

EVC2 p.Trp337Arg (c.1009T>A) is classified Uncertain significance in EVC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-14). AlphaMissense: likely benign (0.0999); Ultra-rare (popmax 0.0516%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EVC2 p.Trp337Arg (c.1009T>A)?

EVC2 p.Trp337Arg (c.1009T>A) is associated with Inborn genetic diseases, acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Trp337Arg (c.1009T>A) in the general population?

EVC2 p.Trp337Arg (c.1009T>A) is ultra-rare (popmax 0.0516%, nfe) (gnomAD).

What do computational predictors say about EVC2 p.Trp337Arg (c.1009T>A)?

AlphaMissense predicts likely benign (score 0.0999) — an in-silico prediction, not a clinical call.

EVC2 p.Trp337Arg

c.1009T>A · rs201555920 · VCV663968

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0999 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0999	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -4.15	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 3.3	GERP -1.3, phastCons 0.41
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	12.65	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0516% European (non-Finnish) · 609/1,179,988 alleles

Filtering AF 0.0482% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0468%

Overall 0.0385% 622/1,614,000 alleles · ultra-rare exomes 609/1,461,794 · genomes 13/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0516%	1,938
Remaining individualsnot grpmax-eligible	0.0176%	5,681
African / African-American	0.00267%	37,460

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.Trp337Arg
Coding: c.1009T>A
MANE Select: NM_147127
dbSNP: rs201555920
Type: single nucleotide variant
Location: chr4:5663243 (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 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
EVC2 c.450+2T>C Likely pathogenic ★★ same condition
EVC2 c.451-2A>G 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-trp337arg (accessed [today's date]).

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