Is EVC2 p.Ser839= (c.2517A>G) pathogenic?

EVC2 p.Ser839= (c.2517A>G) is classified Conflicting classifications of pathogenicity in EVC2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-22). Very rare (popmax 0.00911%, nfe); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Ser839= (c.2517A>G)?

EVC2 p.Ser839= (c.2517A>G) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Ser839= (c.2517A>G) in the general population?

EVC2 p.Ser839= (c.2517A>G) is very rare (popmax 0.00911%, nfe) (gnomAD).

EVC2 p.Ser839=

c.2517A>G · rs756424912 · VCV284908

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00911%, nfe)

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -3.3
Overall
CADD	0.241	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00911% European (non-Finnish) · 107/1,174,634 alleles

Filtering AF 0.00769% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00712%

Overall 0.00699% 112/1,603,042 alleles · very rare exomes 107/1,450,900 · genomes 5/152,142 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00911%	10,978
Admixed American	0.00341%	29,295
African / African-American	0.00268%	37,318
Remaining individualsnot grpmax-eligible	0.00161%	62,108

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: EVC2
Protein: p.Ser839=
Coding: c.2517A>G
MANE Select: NM_147127
dbSNP: rs756424912
Type: single nucleotide variant
Location: chr4:5618667 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.33

Full EVC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acrofacial dysostosis, Weyers type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC2 p.Ser839Ter Pathogenic ★ same residue
EVC2 c.2046+1G>A Likely pathogenic ★★ same condition
EVC2 c.2047-2A>G Likely pathogenic ★★ same condition
EVC2 c.229-1G>T Likely pathogenic ★★ same condition
EVC2 c.229-2A>G Likely pathogenic ★★ same condition
EVC2 c.3360+1G>A Pathogenic ★★ same condition
EVC2 c.3659+2T>C Pathogenic/Likely pathogenic ★★ same condition
EVC2 c.450+2T>C 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/evc2-p-ser839 (accessed [today's date]).

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