Is EVC p.Arg753Gln (c.2258G>A) pathogenic?

EVC p.Arg753Gln (c.2258G>A) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-19). AlphaMissense: likely benign (0.0957); Rare (popmax 0.125%, afr); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Arg753Gln (c.2258G>A)?

EVC p.Arg753Gln (c.2258G>A) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC p.Arg753Gln (c.2258G>A) in the general population?

EVC p.Arg753Gln (c.2258G>A) is rare (popmax 0.125%, afr) (gnomAD).

What do computational predictors say about EVC p.Arg753Gln (c.2258G>A)?

AlphaMissense predicts likely benign (score 0.0957) — an in-silico prediction, not a clinical call.

EVC p.Arg753Gln

c.2258G>A · rs146739019 · VCV2037675

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0957 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.125%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.0957	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -6.02	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 6.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	21.1	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 0.125% African / African-American · 94/74,992 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0972%

Overall 0.00751% 121/1,611,136 alleles · rare exomes 71/1,458,802 · genomes 50/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.125%	798
Remaining individualsnot grpmax-eligible	0.0144%	6,923
Admixed American	0.00833%	12,002
South Asian	0.0022%	45,435
European (non-Finnish)	0.000932%	107,267

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.Arg753Gln
Coding: c.2258G>A
MANE Select: NM_153717
dbSNP: rs146739019
Type: single nucleotide variant
Location: chr4:5798746 (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.Arg753Trp 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
EVC c.1886+5G>T Pathogenic/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-arg753gln (accessed [today's date]).

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