Is EVC2 p.Ser144Phe (c.431C>T) pathogenic?

EVC2 p.Ser144Phe (c.431C>T) is classified Uncertain significance in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-21). AlphaMissense: likely benign (0.1256); Absent from gnomAD v4.1; Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Ser144Phe (c.431C>T)?

EVC2 p.Ser144Phe (c.431C>T) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Ser144Phe (c.431C>T) in the general population?

EVC2 p.Ser144Phe (c.431C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EVC2 p.Ser144Phe (c.431C>T)?

AlphaMissense predicts likely benign (score 0.1256) — an in-silico prediction, not a clinical call.

EVC2 p.Ser144Phe

c.431C>T · rs1721324770 · VCV2949127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1256 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.1256	likely benign
REVEL	0.433	indeterminate
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	GERP 0.61, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Ser144Phe
Coding: c.431C>T
MANE Select: NM_147127
dbSNP: rs1721324770
Type: single nucleotide variant
Location: chr4:5694354 (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

acrofacial dysostosis, Weyers type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ellis-van Creveld syndrome

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-ser144phe (accessed [today's date]).

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