Is EVC2 p.Leu1085= (c.3253C>T) pathogenic?

EVC2 p.Leu1085= (c.3253C>T) is classified Benign in EVC2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-09). Common (popmax 7.89%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Leu1085= (c.3253C>T)?

EVC2 p.Leu1085= (c.3253C>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

EVC2 p.Leu1085=

Q: How common is EVC2 p.Leu1085= (c.3253C>T) in the general population?

EVC2 p.Leu1085= (c.3253C>T) is common (popmax 7.89%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3253C>T · rs112554914 · VCV348986

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 7.89%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.4	GERP 0.92, phastCons 1
Overall
CADD	3.728	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.89% European (non-Finnish) · 93,073/1,180,024 alleles

Filtering AF 7.84% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.83%

Overall 6.99% 112,803/1,614,150 alleles · common exomes 104,918/1,461,888 · genomes 7,885/152,262 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	10.4%	10
European (non-Finnish)grpmax	7.89%	13
South Asian	6.24%	16
Remaining individualsnot grpmax-eligible	6.01%	17
Amishnot grpmax-eligible	5.81%	17
Ashkenazi Jewishnot grpmax-eligible	3.98%	25
Middle Eastern	3.23%	31
Admixed American	2.28%	44
African / African-American	1.12%	90
East Asian	0.0357%	2,804

Finnish 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.Leu1085=
Coding: c.3253C>T
MANE Select: NM_147127
dbSNP: rs112554914
Type: single nucleotide variant
Location: chr4:5576259 (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.Leu1085fs 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
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-leu1085 (accessed [today's date]).

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