Is EVC2 p.Ala1137= (c.3411C>T) pathogenic?

EVC2 p.Ala1137= (c.3411C>T) is classified Conflicting classifications of pathogenicity in EVC2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-24). Rare (popmax 0.145%, nfe); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Ala1137= (c.3411C>T)?

EVC2 p.Ala1137= (c.3411C>T) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Ala1137= (c.3411C>T) in the general population?

EVC2 p.Ala1137= (c.3411C>T) is rare (popmax 0.145%, nfe) (gnomAD).

EVC2 p.Ala1137=

c.3411C>T · rs144532809 · VCV772299

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.145%, nfe)

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP 1, phastCons 0.99
Overall
CADD	5.512	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.145% European (non-Finnish) · 1,713/1,179,626 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.123% 1,981/1,608,676 alleles · rare exomes 1,772/1,456,412 · genomes 209/152,264 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.74%	36
Finnishnot grpmax-eligible	0.262%	381
European (non-Finnish)grpmax	0.145%	689
Remaining individualsnot grpmax-eligible	0.0834%	1,199
Admixed American	0.0234%	4,282
African / African-American	0.0227%	4,413
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,504

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala1137=
Coding: c.3411C>T
MANE Select: NM_147127
dbSNP: rs144532809
Type: single nucleotide variant
Location: chr4:5568590 (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.Ala1137Val Uncertain significance ★ ⚠ same residue
EVC2 p.Ala1137Pro Uncertain significance ★ ⚠ 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-ala1137 (accessed [today's date]).

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