Is EVC2 p.Phe302Ile (c.904T>A) pathogenic?

EVC2 p.Phe302Ile (c.904T>A) is classified Conflicting classifications of pathogenicity in EVC2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-11). AlphaMissense: ambiguous (0.4617); Rare (popmax 0.759%, mid); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Phe302Ile (c.904T>A)?

EVC2 p.Phe302Ile (c.904T>A) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC2 p.Phe302Ile (c.904T>A) in the general population?

EVC2 p.Phe302Ile (c.904T>A) is rare (popmax 0.759%, mid) (gnomAD).

What do computational predictors say about EVC2 p.Phe302Ile (c.904T>A)?

AlphaMissense predicts ambiguous (score 0.4617) — an in-silico prediction, not a clinical call.

EVC2 p.Phe302Ile

c.904T>A · rs138728350 · VCV461811

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.4617 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.759%, mid)

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.4617	ambiguous
REVEL	0.468	indeterminate
SaProt	LLR -7.00	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 0.69, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	22.9	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 0.759% Middle Eastern · 46/6,062 alleles

Filtering AF 0.585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.523%

Overall 0.0449% 725/1,614,156 alleles · rare exomes 600/1,461,878 · genomes 125/152,278 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.759%	132
Amishnot grpmax-eligible	0.22%	455
Admixed American	0.183%	546
South Asian	0.105%	949
Remaining individualsnot grpmax-eligible	0.072%	1,389
European (non-Finnish)	0.0351%	2,850
African / African-American	0.012%	8,338
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869

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.Phe302Ile
Coding: c.904T>A
MANE Select: NM_147127
dbSNP: rs138728350
Type: single nucleotide variant
Location: chr4:5665616 (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

Ellis-van Creveld syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrofacial dysostosis, Weyers type

Similar variants

EVC2 p.Phe302fs Pathogenic ★ 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
EVC2 c.450+2T>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/evc2-p-phe302ile (accessed [today's date]).

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