Is EVC2 p.Met759Val (c.2275A>G) pathogenic?

EVC2 p.Met759Val (c.2275A>G) is classified Uncertain significance in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-14). AlphaMissense: likely benign (0.0645); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EVC2 p.Met759Val (c.2275A>G)?

EVC2 p.Met759Val (c.2275A>G) is associated with Inborn genetic diseases (ClinVar).

How common is EVC2 p.Met759Val (c.2275A>G) in the general population?

EVC2 p.Met759Val (c.2275A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about EVC2 p.Met759Val (c.2275A>G)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

EVC2 p.Met759Val

c.2275A>G · VCV3510665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -4.57	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 -0.71	GERP -4.1
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	0.943	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,020 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,074 alleles · very rare exomes 4/1,461,886 · genomes 0/152,188 · joint denominator

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.Met759Val
Coding: c.2275A>G
MANE Select: NM_147127
Type: single nucleotide variant
Location: chr4:5622763 (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

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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-met759val (accessed [today's date]).

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