Is EVC2 p.Ala245Ser (c.733G>T) pathogenic?

EVC2 p.Ala245Ser (c.733G>T) is classified Likely benign in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: likely benign (0.0798); Very rare (popmax 0.00246%, nfe); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Ala245Ser (c.733G>T)?

EVC2 p.Ala245Ser (c.733G>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC2 p.Ala245Ser (c.733G>T) in the general population?

EVC2 p.Ala245Ser (c.733G>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about EVC2 p.Ala245Ser (c.733G>T)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

EVC2 p.Ala245Ser

c.733G>T · rs530937415 · VCV1107034

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -4.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.37	GERP -1.6, phastCons 0.47
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	1.799	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,180,024 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00198% 32/1,614,030 alleles · very rare exomes 30/1,461,846 · genomes 2/152,184 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)grpmax	0.00246%	40,690
Finnishnot grpmax-eligible	0.00156%	64,016

Remaining individuals 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: EVC2
Protein: p.Ala245Ser
Coding: c.733G>T
MANE Select: NM_147127
dbSNP: rs530937415
Type: single nucleotide variant
Location: chr4:5685453 (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.Ala245Glu Uncertain significance ★ ⚠ same residue
EVC2 p.Ala245= Likely benign ★ 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

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-ala245ser (accessed [today's date]).

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