Is EVC2 p.Gly781= (c.2343C>T) pathogenic?

EVC2 p.Gly781= (c.2343C>T) is classified Uncertain significance in EVC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-01-03). Very rare (popmax 0.00941%, nfe); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Gly781= (c.2343C>T)?

EVC2 p.Gly781= (c.2343C>T) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Gly781= (c.2343C>T) in the general population?

EVC2 p.Gly781= (c.2343C>T) is very rare (popmax 0.00941%, nfe) (gnomAD).

EVC2 p.Gly781=

c.2343C>T · rs762082443 · VCV552863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00941%, nfe)

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.96	donor gain · deltas
Pangolin	Δ0.66	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP -1.3, phastCons 1
Overall
CADD	19.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00941% European (non-Finnish) · 111/1,180,016 alleles

Filtering AF 0.00791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00744%

Overall 0.00725% 117/1,613,932 alleles · very rare exomes 115/1,461,880 · genomes 2/152,052 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00941%	10,631
Finnishnot grpmax-eligible	0.00625%	16,007
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Gly781=
Coding: c.2343C>T
MANE Select: NM_147127
dbSNP: rs762082443
Type: single nucleotide variant
Location: chr4:5622695 (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.Gly781Ser Uncertain significance ★ ⚠ 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-gly781 (accessed [today's date]).

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