Is EVC p.Arg652His (c.1955G>A) pathogenic?

EVC p.Arg652His (c.1955G>A) is classified Uncertain significance in EVC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-22). AlphaMissense: likely benign (0.1863); Very rare (popmax 0.00439%, sas); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Arg652His (c.1955G>A)?

EVC p.Arg652His (c.1955G>A) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC p.Arg652His (c.1955G>A) in the general population?

EVC p.Arg652His (c.1955G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about EVC p.Arg652His (c.1955G>A)?

AlphaMissense predicts likely benign (score 0.1863) — an in-silico prediction, not a clinical call.

EVC p.Arg652His

c.1955G>A · rs765024763 · VCV1385744

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.1863	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -7.60	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	25.2	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

Grpmax group 0.00439% South Asian · 4/91,086 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00267% 43/1,613,408 alleles · very rare exomes 41/1,461,168 · genomes 2/152,240 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,772
European (non-Finnish)	0.00322%	31,053
Admixed American	0.00167%	60,006

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.Arg652His
Coding: c.1955G>A
MANE Select: NM_153717
dbSNP: rs765024763
Type: single nucleotide variant
Location: chr4:5797090 (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

Also linked: acrofacial dysostosis, Weyers type

Similar variants

EVC p.Arg652= Conflicting classifications of pathogenicity ★ same residue
EVC p.Arg652Cys 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
EVC c.1886+5G>A 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-arg652his (accessed [today's date]).

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