Is EVC p.Ser83= (c.249A>G) pathogenic?

EVC p.Ser83= (c.249A>G) is classified Benign in EVC (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-05-08). Common (popmax 16.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Ser83= (c.249A>G)?

EVC p.Ser83= (c.249A>G) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

EVC p.Ser83=

Q: How common is EVC p.Ser83= (c.249A>G) in the general population?

EVC p.Ser83= (c.249A>G) is common (popmax 16.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.249A>G · rs35870680 · VCV262776

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 16.9%, mid) — too common for a highly-penetrant pathogenic allele

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 -4	GERP -3
Overall
CADD	0.402	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.9% Middle Eastern · 1,023/6,062 alleles

Filtering AF 16% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.7%

Overall 13.1% 210,888/1,614,116 alleles · common exomes 195,561/1,461,846 · genomes 15,327/152,270 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	19.7%	5
Middle Easterngrpmax	16.9%	6
Amishnot grpmax-eligible	15.8%	6
European (non-Finnish)	14.4%	7
Finnishnot grpmax-eligible	13.3%	8
South Asian	12.8%	8
Remaining individualsnot grpmax-eligible	12.8%	8
Admixed American	7.28%	14
African / African-American	2.48%	40
East Asian	0.0535%	1,870

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser83=
Coding: c.249A>G
MANE Select: NM_153717
dbSNP: rs35870680
Type: single nucleotide variant
Location: chr4:5719322 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49
Residue 83: the 'disordered' region

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.Ser83Ter Pathogenic ★ same residue
EVC p.Ser83Leu 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-ser83 (accessed [today's date]).

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