Is EVC p.Ser253= (c.759A>G) pathogenic?

EVC p.Ser253= (c.759A>G) is classified Likely benign in EVC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-05). Ultra-rare (popmax 0.0883%, mid); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Ser253= (c.759A>G)?

EVC p.Ser253= (c.759A>G) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC p.Ser253= (c.759A>G) in the general population?

EVC p.Ser253= (c.759A>G) is ultra-rare (popmax 0.0883%, mid) (gnomAD).

EVC p.Ser253=

c.759A>G · rs201105095 · VCV707150

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0883%, mid)

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.9	GERP -3.3
Overall
CADD	2.428	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0883% Middle Eastern · 5/5,660 alleles

Filtering AF 0.0347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0225%

Overall 0.0104% 163/1,570,350 alleles · ultra-rare exomes 147/1,418,142 · genomes 16/152,208 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0883%	1,132
European (non-Finnish)	0.0126%	7,927
Remaining individualsnot grpmax-eligible	0.00986%	10,140
African / African-American	0.00674%	14,836
Admixed American	0.00501%	19,941

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.Ser253=
Coding: c.759A>G
MANE Select: NM_153717
dbSNP: rs201105095
Type: single nucleotide variant
Location: chr4:5741772 (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.Ser253Ter 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
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-ser253 (accessed [today's date]).

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