Is MAP2K2 p.Ile351Val (c.1051A>G) pathogenic?

MAP2K2 p.Ile351Val (c.1051A>G) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-24). AlphaMissense: likely benign (0.0764); No allele count reported in gnomAD v4.1 (AN 1,570,486); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Ile351Val (c.1051A>G)?

MAP2K2 p.Ile351Val (c.1051A>G) is associated with Cardiovascular phenotype (ClinVar).

How common is MAP2K2 p.Ile351Val (c.1051A>G) in the general population?

MAP2K2 p.Ile351Val (c.1051A>G) is no allele count reported in gnomAD v4.1 (AN 1,570,486) (gnomAD).

What do computational predictors say about MAP2K2 p.Ile351Val (c.1051A>G)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ile351Val

c.1051A>G · VCV4103132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,570,486)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -5.19	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 3.4	GERP 0.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	19.87	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

No allele count reported in gnomAD v4.1 (AN 1,570,486). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MAP2K2
Protein: p.Ile351Val
Coding: c.1051A>G
MANE Select: NM_030662
Type: single nucleotide variant
Location: chr19:4094494 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 351: the protein kinase domain

Full MAP2K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP2K2 p.Ile351Leu Uncertain significance ★ ⚠ same residue
MAP2K2 p.Ile351= Likely benign ★ same residue
MAP2K2 p.Gly132Asp Pathogenic/Likely pathogenic ★★ same condition
MAP2K2 c.450+5G>A Uncertain significance ★★ same condition
MAP2K2 p.Ala355Val Uncertain significance ★★ ⚠ same condition
MAP2K2 p.Ala358Val Uncertain significance ★★ ⚠ same condition
MAP2K2 p.Ala380Val Uncertain significance ★★ ⚠ same condition
MAP2K2 p.Arg193Gln Uncertain significance ★★ ⚠ 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/map2k2-p-ile351val (accessed [today's date]).

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