Is EVC p.Thr757Pro (c.2269A>C) pathogenic?

EVC p.Thr757Pro (c.2269A>C) is classified Uncertain significance in EVC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.1139); Very rare (popmax 6.21e-05%); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Thr757Pro (c.2269A>C)?

EVC p.Thr757Pro (c.2269A>C) is associated with Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Thr757Pro (c.2269A>C) in the general population?

EVC p.Thr757Pro (c.2269A>C) is very rare (popmax 6.21e-05%) (gnomAD).

What do computational predictors say about EVC p.Thr757Pro (c.2269A>C)?

AlphaMissense predicts likely benign (score 0.1139) — an in-silico prediction, not a clinical call.

EVC p.Thr757Pro

c.2269A>C · VCV4067530

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1139 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.21e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.1139	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -11.55	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -2, phastCons 0.98
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	17.49	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 6.21e-05%

Overall 6.21e-05% 1/1,611,264 alleles · very rare exomes 1/1,458,926 · genomes 0/152,338 · joint denominator

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.Thr757Pro
Coding: c.2269A>C
MANE Select: NM_153717
Type: single nucleotide variant
Location: chr4:5798757 (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.Thr757= Likely benign ★ same residue
EVC p.Thr757Asn 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-thr757pro (accessed [today's date]).

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