Is EVC2 p.Leu514= (c.1542C>T) pathogenic?

EVC2 p.Leu514= (c.1542C>T) is classified Likely benign in EVC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-30). Very rare (popmax 0.00763%, nfe); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Leu514= (c.1542C>T)?

EVC2 p.Leu514= (c.1542C>T) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Leu514= (c.1542C>T) in the general population?

EVC2 p.Leu514= (c.1542C>T) is very rare (popmax 0.00763%, nfe) (gnomAD).

EVC2 p.Leu514=

c.1542C>T · rs376252506 · VCV512537

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00763%, 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 -6.6	GERP -3.5
Overall
CADD	0.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00763% European (non-Finnish) · 90/1,180,050 alleles

Filtering AF 0.00631% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00584%

Overall 0.00613% 99/1,614,098 alleles · very rare exomes 98/1,461,886 · genomes 1/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00763%	13,112
South Asian	0.00439%	22,770
Admixed American	0.00333%	30,003
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00133%	74,934

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.Leu514=
Coding: c.1542C>T
MANE Select: NM_147127
dbSNP: rs376252506
Type: single nucleotide variant
Location: chr4:5631961 (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.Leu514Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
EVC2 p.Leu514fs 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

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-leu514 (accessed [today's date]).

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