Is EVC2 p.Leu724= (c.2172G>T) pathogenic?

EVC2 p.Leu724= (c.2172G>T) is classified Likely benign in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). Very rare (popmax 0.00223%, eas); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Leu724= (c.2172G>T)?

EVC2 p.Leu724= (c.2172G>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC2 p.Leu724= (c.2172G>T) in the general population?

EVC2 p.Leu724= (c.2172G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

EVC2 p.Leu724=

c.2172G>T · rs546009991 · VCV1140593

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 0.33	GERP -2.5, phastCons 0.99
Overall
CADD	5.976	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,614,058 alleles · very rare exomes 7/1,461,878 · genomes 2/152,180 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
Finnishnot grpmax-eligible	0.00156%	64,024
European (non-Finnish)	0.000593%	168,579

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.Leu724=
Coding: c.2172G>T
MANE Select: NM_147127
dbSNP: rs546009991
Type: single nucleotide variant
Location: chr4:5622866 (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

Ellis-van Creveld syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrofacial dysostosis, Weyers type

Similar variants

EVC2 p.Leu724_Gln725insGluGluLeu 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-leu724 (accessed [today's date]).

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