Is EVC p.Leu28Pro (c.83T>C) pathogenic?

EVC p.Leu28Pro (c.83T>C) is classified Uncertain significance in EVC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-04). AlphaMissense: ambiguous (0.4388); Very rare (popmax 0.00429%, sas); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Leu28Pro (c.83T>C)?

EVC p.Leu28Pro (c.83T>C) is associated with Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Leu28Pro (c.83T>C) in the general population?

EVC p.Leu28Pro (c.83T>C) is very rare (popmax 0.00429%, sas) (gnomAD).

What do computational predictors say about EVC p.Leu28Pro (c.83T>C)?

AlphaMissense predicts ambiguous (score 0.4388) — an in-silico prediction, not a clinical call.

EVC p.Leu28Pro

c.83T>C · rs1256100832 · VCV904931

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4388 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00429%, sas)

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.4388	ambiguous
REVEL	0.394	indeterminate
SaProt	LLR -10.16	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.2, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	22.3	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 0.00429% South Asian · 1/23,298 alleles

Overall 0.00019% 2/1,053,642 alleles · very rare exomes 1/905,988 · genomes 1/147,654 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00429%	23,298
European (non-Finnish)	0.000114%	877,178

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.Leu28Pro
Coding: c.83T>C
MANE Select: NM_153717
dbSNP: rs1256100832
Type: single nucleotide variant
Location: chr4:5711463 (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

Similar variants

EVC p.Leu28= Likely benign ★ same residue
EVC p.Leu28Met 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

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-leu28pro (accessed [today's date]).

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