Is EVC p.Arg22Pro (c.65G>C) pathogenic?

EVC p.Arg22Pro (c.65G>C) is classified Uncertain significance in EVC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-26). AlphaMissense: likely benign (0.1421); No allele count reported in gnomAD v4.1 (AN 1,025,408); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Arg22Pro (c.65G>C)?

EVC p.Arg22Pro (c.65G>C) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Arg22Pro (c.65G>C) in the general population?

EVC p.Arg22Pro (c.65G>C) is no allele count reported in gnomAD v4.1 (AN 1,025,408) (gnomAD).

What do computational predictors say about EVC p.Arg22Pro (c.65G>C)?

AlphaMissense predicts likely benign (score 0.1421) — an in-silico prediction, not a clinical call.

EVC p.Arg22Pro

c.65G>C · rs2151767266 · VCV1224318

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1421 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,025,408)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.1421	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.096	GERP -0.96
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	15.35	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

No allele count reported in gnomAD v4.1 (AN 1,025,408). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: EVC
Protein: p.Arg22Pro
Coding: c.65G>C
MANE Select: NM_153717
dbSNP: rs2151767266
Type: single nucleotide variant
Location: chr4:5711445 (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

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

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC p.Arg22= Likely benign ★ same residue
EVC p.Arg22Trp Uncertain significance ⚠ same residue
EVC p.Arg22fs Likely pathogenic ★ 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-arg22pro (accessed [today's date]).

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