Is MAP2K2 p.Ile111Phe (c.331A>T) pathogenic?

MAP2K2 p.Ile111Phe (c.331A>T) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-19). AlphaMissense: likely pathogenic (0.8861); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with MAP2K2 p.Ile111Phe (c.331A>T)?

MAP2K2 p.Ile111Phe (c.331A>T) is associated with RASopathy, cardiofaciocutaneous syndrome 4 (ClinVar).

How common is MAP2K2 p.Ile111Phe (c.331A>T) in the general population?

MAP2K2 p.Ile111Phe (c.331A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K2 p.Ile111Phe (c.331A>T)?

AlphaMissense predicts likely pathogenic (score 0.8861) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ile111Phe

c.331A>T · rs1555698031 · VCV432872

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8861 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.8861	likely pathogenic
REVEL	0.436	indeterminate
SaProt	LLR -13.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.83, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAP2K2
Protein: p.Ile111Phe
Coding: c.331A>T
MANE Select: NM_030662
dbSNP: rs1555698031
Type: single nucleotide variant
Location: chr19:4110628 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 111: the protein kinase domain; an α-helix

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

Disease context

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

Also linked: cardiofaciocutaneous syndrome 4

Similar variants

MAP2K2 p.Ile111Met Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
MAP2K2 p.Phe57Val Pathogenic ★★★ same condition
MAP2K2 p.Pro128Gln Pathogenic ★★★ same condition
MAP2K2 p.Tyr134Cys Likely pathogenic ★★★ same condition
MAP2K2 p.Tyr134His Pathogenic ★★★ same condition
MAP2K2 p.Arg231His 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-ile111phe (accessed [today's date]).

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