Is EVC2 p.Leu18Phe (c.52C>T) pathogenic?

EVC2 p.Leu18Phe (c.52C>T) is classified Benign in EVC2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-06-02). AlphaMissense: likely benign (0.1027); Common (popmax 30.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Leu18Phe (c.52C>T)?

EVC2 p.Leu18Phe (c.52C>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

What do computational predictors say about EVC2 p.Leu18Phe (c.52C>T)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

EVC2 p.Leu18Phe

Q: How common is EVC2 p.Leu18Phe (c.52C>T) in the general population?

EVC2 p.Leu18Phe (c.52C>T) is common (popmax 30.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.52C>T · rs6820907 · VCV262618

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 30.6%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -9.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.05	GERP -2.6, phastCons 0.007
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	15.24	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 30.6% African / African-American · 21,113/69,098 alleles

Filtering AF 30.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 30.1%

Overall 13.3% 200,313/1,505,760 alleles · common exomes 173,268/1,353,784 · genomes 27,045/151,976 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	30.6%	3
Amishnot grpmax-eligible	29.6%	3
East Asian	23.5%	4
Admixed American	20.2%	5
South Asian	18.7%	5
Remaining individualsnot grpmax-eligible	13.5%	7
Finnishnot grpmax-eligible	12%	8
European (non-Finnish)	11.4%	9
Middle Eastern	11.3%	9
Ashkenazi Jewishnot grpmax-eligible	10.3%	10

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.Leu18Phe
Coding: c.52C>T
MANE Select: NM_147127
dbSNP: rs6820907
Type: single nucleotide variant
Location: chr4:5708462 (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.Leu18= Likely benign ★ same residue
EVC2 p.Leu18fs Pathogenic/Likely 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-leu18phe (accessed [today's date]).

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