Is EVC2 p.Pro347Leu (c.1040C>T) pathogenic?

EVC2 p.Pro347Leu (c.1040C>T) is classified Benign/Likely benign in EVC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0651); Low-frequency (popmax 1.13%, sas); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Pro347Leu (c.1040C>T)?

EVC2 p.Pro347Leu (c.1040C>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC2 p.Pro347Leu (c.1040C>T) in the general population?

EVC2 p.Pro347Leu (c.1040C>T) is low-frequency (popmax 1.13%, sas) (gnomAD).

What do computational predictors say about EVC2 p.Pro347Leu (c.1040C>T)?

AlphaMissense predicts likely benign (score 0.0651) — an in-silico prediction, not a clinical call.

EVC2 p.Pro347Leu

c.1040C>T · rs199708349 · VCV767181

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0651 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.13%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.0651	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -6.16	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 1.1	GERP -3.3, phastCons 0.81
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	9.812	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 1.13% South Asian · 1,032/91,070 alleles

Filtering AF 1.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.05%

Overall 0.0697% 1,125/1,614,118 alleles · low-frequency exomes 1,067/1,461,858 · genomes 58/152,260 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.13%	88
Remaining individualsnot grpmax-eligible	0.0752%	1,330
African / African-American	0.00533%	18,756
European (non-Finnish)	0.00356%	28,095

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.Pro347Leu
Coding: c.1040C>T
MANE Select: NM_147127
dbSNP: rs199708349
Type: single nucleotide variant
Location: chr4:5663212 (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.Pro347= 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-pro347leu (accessed [today's date]).

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