Is MAP2K2 p.Ile115Val (c.343A>G) pathogenic?

MAP2K2 p.Ile115Val (c.343A>G) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-28). AlphaMissense: likely pathogenic (0.9112); Very rare (popmax 0.000744%); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Ile115Val (c.343A>G)?

MAP2K2 p.Ile115Val (c.343A>G) is associated with Cardiovascular phenotype (ClinVar).

How common is MAP2K2 p.Ile115Val (c.343A>G) in the general population?

MAP2K2 p.Ile115Val (c.343A>G) is very rare (popmax 0.000744%) (gnomAD).

What do computational predictors say about MAP2K2 p.Ile115Val (c.343A>G)?

AlphaMissense predicts likely pathogenic (score 0.9112) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ile115Val

c.343A>G · VCV4103127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000744%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9112	likely pathogenic
REVEL	0.622	indeterminate
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	24.8	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 0.000744%

Overall 0.000744% 12/1,613,712 alleles · very rare exomes 10/1,461,500 · genomes 2/152,212 · 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: MAP2K2
Protein: p.Ile115Val
Coding: c.343A>G
MANE Select: NM_030662
Type: single nucleotide variant
Location: chr19:4110616 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 115: the protein kinase domain; an α-helix

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.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
MAP2K2 p.Arg193Ter Uncertain significance ★★ same condition
MAP2K2 p.Arg238Trp 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-ile115val (accessed [today's date]).

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