Is EVC p.Arg52Cys (c.154C>T) pathogenic?

EVC p.Arg52Cys (c.154C>T) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-20). AlphaMissense: likely benign (0.2231); Ultra-rare (popmax 0.0774%, afr); Associated with Inborn genetic diseases.

What condition is associated with EVC p.Arg52Cys (c.154C>T)?

EVC p.Arg52Cys (c.154C>T) is associated with Inborn genetic diseases, acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Arg52Cys (c.154C>T) in the general population?

EVC p.Arg52Cys (c.154C>T) is ultra-rare (popmax 0.0774%, afr) (gnomAD).

What do computational predictors say about EVC p.Arg52Cys (c.154C>T)?

AlphaMissense predicts likely benign (score 0.2231) — an in-silico prediction, not a clinical call.

EVC p.Arg52Cys

c.154C>T · rs932851648 · VCV2197559

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2231 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0774%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2231	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP -0.68, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	22.9	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 0.0774% African / African-American · 48/62,020 alleles

Filtering AF 0.0599% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0537%

Overall 0.00427% 50/1,170,376 alleles · ultra-rare exomes 14/1,019,286 · genomes 36/151,090 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0774%	1,292
Admixed American	0.00466%	21,468
European (non-Finnish)	0.000105%	948,677

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.Arg52Cys
Coding: c.154C>T
MANE Select: NM_153717
dbSNP: rs932851648
Type: single nucleotide variant
Location: chr4:5711534 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrofacial dysostosis, Weyers type Ellis-van Creveld syndrome

Similar variants

EVC p.Arg52Gly Uncertain significance ★ ⚠ same residue
EVC p.Arg52= Uncertain significance same residue
EVC p.Arg52fs 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-arg52cys (accessed [today's date]).

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