Is ME2 p.Ile252Val (c.754A>G) pathogenic?

ME2 p.Ile252Val (c.754A>G) is classified Uncertain significance in ME2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-24). AlphaMissense: likely benign (0.1605); Ultra-rare (popmax 0.0329%, amr).

How common is ME2 p.Ile252Val (c.754A>G) in the general population?

ME2 p.Ile252Val (c.754A>G) is ultra-rare (popmax 0.0329%, amr) (gnomAD).

What do computational predictors say about ME2 p.Ile252Val (c.754A>G)?

AlphaMissense predicts likely benign (score 0.1605) — an in-silico prediction, not a clinical call.

ME2 p.Ile252Val

c.754A>G · rs1277740276 · VCV3124761

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1605 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1605	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 51 kb · p 2.7e-05 · regional, not allelic
Overall
CADD	25.0	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 0.0329% Admixed American · 18/54,708 alleles

Filtering AF 0.0212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0176%

Overall 0.00156% 25/1,598,858 alleles · ultra-rare exomes 11/1,446,644 · genomes 14/152,214 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0329%	3,039
South Asian	0.00345%	28,981
Remaining individualsnot grpmax-eligible	0.00323%	30,995
African / African-American	0.00136%	73,748
European (non-Finnish)	8.5e-05%	1,176,534

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: ME2
Protein: p.Ile252Val
Coding: c.754A>G
MANE Select: NM_002396
dbSNP: rs1277740276
Type: single nucleotide variant
Location: chr18:50920475 (GRCh38)
Gene constraint: LOEUF 1.065 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.55 · 19 PDB
Residue 252: a β-strand

Full ME2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ME2 p.Val468= Benign ★★ same type
ME2 p.Ala191Val Uncertain significance ★ ⚠ same type
ME2 p.Ala241Val Uncertain significance ★ ⚠ same type
ME2 p.Ala289Thr Uncertain significance ★ same type
ME2 p.Ala312Val Uncertain significance ★ ⚠ same type
ME2 p.Ala315Asp Uncertain significance ★ ⚠ same type
ME2 p.Ala39Glu Uncertain significance ★ ⚠ same type
ME2 p.Ala517Thr Uncertain significance ★ ⚠ same type

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/me2-p-ile252val (accessed [today's date]).

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