Is EVC p.Pro137Ser (c.409C>T) pathogenic?

EVC p.Pro137Ser (c.409C>T) is classified Uncertain significance in EVC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-01-05). AlphaMissense: likely pathogenic (0.8853); Absent from gnomAD v4.1; Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Pro137Ser (c.409C>T)?

EVC p.Pro137Ser (c.409C>T) is associated with Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Pro137Ser (c.409C>T) in the general population?

EVC p.Pro137Ser (c.409C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EVC p.Pro137Ser (c.409C>T)?

AlphaMissense predicts likely pathogenic (score 0.8853) — an in-silico prediction, not a clinical call.

EVC p.Pro137Ser

c.409C>T · VCV4067571

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8853 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.8853	likely pathogenic · top 2% in EVC
REVEL	0.534	indeterminate
SaProt	LLR -5.08	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EVC
Protein: p.Pro137Ser
Coding: c.409C>T
MANE Select: NM_153717
Type: single nucleotide variant
Location: chr4:5731449 (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.Pro137Thr Uncertain significance ★★ ⚠ same residue
EVC p.Pro137= Likely benign ★★ same residue
EVC p.Pro137Leu 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

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-pro137ser (accessed [today's date]).

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