Is EVC p.Leu366= (c.1096C>T) pathogenic?

EVC p.Leu366= (c.1096C>T) is classified Benign in EVC (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-05-11). Common (popmax 10.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Leu366= (c.1096C>T)?

EVC p.Leu366= (c.1096C>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

EVC p.Leu366=

Q: How common is EVC p.Leu366= (c.1096C>T) in the general population?

EVC p.Leu366= (c.1096C>T) is common (popmax 10.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1096C>T · rs6854138 · VCV262763

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 10.5%, afr) — 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
Constraint at this position
Conservation	phyloP 1.6	GERP 0.94, phastCons 0.9
Overall
CADD	17.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.5% African / African-American · 7,835/74,968 alleles

Filtering AF 10.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.2%

Overall 0.583% 9,411/1,613,968 alleles · common exomes 4,832/1,461,820 · genomes 4,579/152,148 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.5%	10
Admixed American	0.818%	122
Remaining individualsnot grpmax-eligible	0.803%	125
Middle Eastern	0.561%	178
Ashkenazi Jewishnot grpmax-eligible	0.223%	449
European (non-Finnish)	0.039%	2,565
South Asian	0.0242%	4,139
East Asian	0.00223%	44,878

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.Leu366=
Coding: c.1096C>T
MANE Select: NM_153717
dbSNP: rs6854138
Type: single nucleotide variant
Location: chr4:5748304 (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-leu366 (accessed [today's date]).

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