Is EVC2 p.Pro3Ser (c.7C>T) pathogenic?

EVC2 p.Pro3Ser (c.7C>T) is classified Uncertain significance in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-21). AlphaMissense: likely benign (0.0582); Very rare (popmax 0.00147%, afr); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Pro3Ser (c.7C>T)?

EVC2 p.Pro3Ser (c.7C>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC2 p.Pro3Ser (c.7C>T) in the general population?

EVC2 p.Pro3Ser (c.7C>T) is very rare (popmax 0.00147%, afr) (gnomAD).

What do computational predictors say about EVC2 p.Pro3Ser (c.7C>T)?

AlphaMissense predicts likely benign (score 0.0582) — an in-silico prediction, not a clinical call.

EVC2 p.Pro3Ser

c.7C>T · VCV3749222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.0582	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -6.42	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 -0.061	GERP -2.6
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	10.25	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 0.00147% African / African-American · 1/67,970 alleles

Overall 0.000136% 2/1,474,744 alleles · very rare exomes 2/1,322,552 · genomes 0/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00147%	67,970
European (non-Finnish)	8.92e-05%	1,120,746

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.Pro3Ser
Coding: c.7C>T
MANE Select: NM_147127
Type: single nucleotide variant
Location: chr4:5708507 (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.Pro3= 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
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-pro3ser (accessed [today's date]).

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