Is EVC2 p.Ile652Val (c.1954A>G) pathogenic?

EVC2 p.Ile652Val (c.1954A>G) is classified Conflicting classifications of pathogenicity in EVC2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-03). AlphaMissense: likely benign (0.0712); Low-frequency (popmax 1.05%, afr); Associated with Inborn genetic diseases.

What condition is associated with EVC2 p.Ile652Val (c.1954A>G)?

EVC2 p.Ile652Val (c.1954A>G) is associated with Inborn genetic diseases, acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Ile652Val (c.1954A>G) in the general population?

EVC2 p.Ile652Val (c.1954A>G) is low-frequency (popmax 1.05%, afr) (gnomAD).

What do computational predictors say about EVC2 p.Ile652Val (c.1954A>G)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

EVC2 p.Ile652Val

c.1954A>G · rs144670544 · VCV391013

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.05%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -7.54	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 -0.76	GERP -3.8
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	0.942	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 1.05% African / African-American · 789/75,030 alleles

Filtering AF 0.991% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.966%

Overall 0.0539% 870/1,614,066 alleles · low-frequency exomes 460/1,461,830 · genomes 410/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.05%	95
Remaining individualsnot grpmax-eligible	0.0688%	1,454
Admixed American	0.0417%	2,400
South Asian	0.0011%	91,076
European (non-Finnish)	0.00102%	98,332

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.Ile652Val
Coding: c.1954A>G
MANE Select: NM_147127
dbSNP: rs144670544
Type: single nucleotide variant
Location: chr4:5625841 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrofacial dysostosis, Weyers type Ellis-van Creveld syndrome

Similar variants

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
EVC2 c.451-2A>G 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-ile652val (accessed [today's date]).

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