Is EVC2 p.Cys458Trp (c.1374T>G) pathogenic?

EVC2 p.Cys458Trp (c.1374T>G) is classified Uncertain significance in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-26). AlphaMissense: ambiguous (0.5406); Absent from gnomAD v4.1; Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Cys458Trp (c.1374T>G)?

EVC2 p.Cys458Trp (c.1374T>G) is associated with Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Cys458Trp (c.1374T>G) in the general population?

EVC2 p.Cys458Trp (c.1374T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EVC2 p.Cys458Trp (c.1374T>G)?

AlphaMissense predicts ambiguous (score 0.5406) — an in-silico prediction, not a clinical call.

EVC2 p.Cys458Trp

c.1374T>G · rs1717255624 · VCV1027772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5406 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.5406	ambiguous · top 10% in EVC2
REVEL	0.555	indeterminate
SaProt	LLR -6.09	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.3	GERP -2.7
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	19.11	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: EVC2
Protein: p.Cys458Trp
Coding: c.1374T>G
MANE Select: NM_147127
dbSNP: rs1717255624
Type: single nucleotide variant
Location: chr4:5640610 (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

Similar variants

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
EVC2 c.450+2T>C Likely pathogenic ★★ same condition
EVC2 c.451-2A>G 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-cys458trp (accessed [today's date]).

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