Is EVC2 p.Val1255fs (c.3762del) pathogenic?

EVC2 p.Val1255fs (c.3762del) is classified Pathogenic in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-18). Very rare (popmax 0.00133%, afr); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Val1255fs (c.3762del)?

EVC2 p.Val1255fs (c.3762del) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Val1255fs (c.3762del) in the general population?

EVC2 p.Val1255fs (c.3762del) is very rare (popmax 0.00133%, afr) (gnomAD).

EVC2 p.Val1255fs

c.3762del · rs1577093258 · VCV639672

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (22 of 22) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.12	GERP -2.2, phastCons 0.005
Overall
CADD	16.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,946 alleles

Overall 0.000124% 2/1,614,112 alleles · very rare exomes 1/1,461,886 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-Americangrpmax	0.00133%	74,946

Remaining individuals 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.Val1255fs
Coding: c.3762del
MANE Select: NM_147127
dbSNP: rs1577093258
Type: Deletion
Location: chr4:5563013 (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 c.222_228+21del Likely pathogenic ★★ same condition
EVC2 c.3361-2del Pathogenic/Likely pathogenic ★★ same condition
EVC2 c.871-2_894del Pathogenic ★★ same condition
EVC2 p.Ala69fs Pathogenic/Likely pathogenic ★★ same condition
EVC2 p.Arg274fs Pathogenic/Likely pathogenic ★★ same condition
EVC2 p.Arg463fs Pathogenic ★★ same condition
EVC2 p.Gly1136fs Pathogenic ★★ same condition
EVC2 p.Leu150fs 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-val1255fs (accessed [today's date]).

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