Is EVC p.Arg576Gln (c.1727G>A) pathogenic?

EVC p.Arg576Gln (c.1727G>A) is classified Benign/Likely benign in EVC (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-05-08). AlphaMissense: likely benign (0.0995); Common (popmax 47.7%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Arg576Gln (c.1727G>A)?

EVC p.Arg576Gln (c.1727G>A) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

What do computational predictors say about EVC p.Arg576Gln (c.1727G>A)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

EVC p.Arg576Gln

Q: How common is EVC p.Arg576Gln (c.1727G>A) in the general population?

EVC p.Arg576Gln (c.1727G>A) is common (popmax 47.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1727G>A · rs1383180 · VCV262768

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 47.7%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -7.79	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 6.5	GERP 0.72, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	25.4	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 47.7% Admixed American · 28,565/59,934 alleles

Filtering AF 47.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 47%

Overall 34.6% 558,112/1,613,550 alleles · common exomes 509,331/1,461,470 · genomes 48,781/152,080 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	47.7%	2
Ashkenazi Jewishnot grpmax-eligible	38.8%	3
European (non-Finnish)	35.9%	3
Remaining individualsnot grpmax-eligible	34.9%	3
Middle Eastern	34.3%	3
Finnishnot grpmax-eligible	33.9%	3
East Asian	30.7%	3
Amishnot grpmax-eligible	23.6%	4
South Asian	22.7%	4
African / African-American	19.6%	5

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.Arg576Gln
Coding: c.1727G>A
MANE Select: NM_153717
dbSNP: rs1383180
Type: single nucleotide variant
Location: chr4:5783715 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49
Residue 576: a UniProt-annotated variant site (in)

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.Arg576Leu Uncertain significance ★★ ⚠ same residue
EVC p.Arg576Trp 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-arg576gln (accessed [today's date]).

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