Is EVC p.Leu328Phe (c.982C>T) pathogenic?

EVC p.Leu328Phe (c.982C>T) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2394); Rare (popmax 0.245%, eas); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Leu328Phe (c.982C>T)?

EVC p.Leu328Phe (c.982C>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC p.Leu328Phe (c.982C>T) in the general population?

EVC p.Leu328Phe (c.982C>T) is rare (popmax 0.245%, eas) (gnomAD).

What do computational predictors say about EVC p.Leu328Phe (c.982C>T)?

AlphaMissense predicts likely benign (score 0.2394) — an in-silico prediction, not a clinical call.

EVC p.Leu328Phe

c.982C>T · rs199916502 · VCV349170

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2394 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.245%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.2394	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -11.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	22.1	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 0.245% East Asian · 110/44,882 alleles

Filtering AF 0.208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.194%

Overall 0.00725% 117/1,614,228 alleles · rare exomes 94/1,461,892 · genomes 23/152,336 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.245%	408
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)	0.000339%	295,012

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.Leu328Phe
Coding: c.982C>T
MANE Select: NM_153717
dbSNP: rs199916502
Type: single nucleotide variant
Location: chr4:5748190 (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 p.Leu328Pro Uncertain significance ★ ⚠ same residue
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

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-leu328phe (accessed [today's date]).

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