Is EVC p.Leu356= (c.1068A>G) pathogenic?

EVC p.Leu356= (c.1068A>G) is classified Benign in EVC (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-05-08). Common (popmax 34%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Leu356= (c.1068A>G)?

EVC p.Leu356= (c.1068A>G) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

EVC p.Leu356=

Q: How common is EVC p.Leu356= (c.1068A>G) in the general population?

EVC p.Leu356= (c.1068A>G) is common (popmax 34%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1068A>G · rs33929747 · VCV262762

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 34%, 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	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.24	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -0.78	GERP -3.9
Overall
CADD	2.109	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 34% European (non-Finnish) · 401,182/1,179,868 alleles

Filtering AF 33.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 33.9%

Overall 31.4% 507,083/1,613,844 alleles · common exomes 466,536/1,461,752 · genomes 40,547/152,092 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	40.9%	2
European (non-Finnish)grpmax	34%	3
Admixed American	33.7%	3
Middle Eastern	32.7%	3
Remaining individualsnot grpmax-eligible	31.4%	3
Finnishnot grpmax-eligible	29.9%	3
Amishnot grpmax-eligible	27.3%	4
South Asian	19.1%	5
East Asian	17.3%	6
African / African-American	9.9%	10

Ashkenazi Jewish 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: EVC
Protein: p.Leu356=
Coding: c.1068A>G
MANE Select: NM_153717
dbSNP: rs33929747
Type: single nucleotide variant
Location: chr4:5748276 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49

Full EVC 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

EVC c.1098+1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.175-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1886+1G>C Likely pathogenic ★★ same condition
EVC c.1886+5G>A Pathogenic ★★ same condition
EVC c.1886+5G>T Pathogenic/Likely pathogenic ★★ same condition
EVC c.2304+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/evc-p-leu356 (accessed [today's date]).

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