Is MAP2K2 p.Ile97Phe (c.289A>T) pathogenic?

MAP2K2 p.Ile97Phe (c.289A>T) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.3352); Very rare (popmax 0.005%, nfe); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ile97Phe (c.289A>T)?

MAP2K2 p.Ile97Phe (c.289A>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ile97Phe (c.289A>T) in the general population?

MAP2K2 p.Ile97Phe (c.289A>T) is very rare (popmax 0.005%, nfe) (gnomAD).

What do computational predictors say about MAP2K2 p.Ile97Phe (c.289A>T)?

AlphaMissense predicts likely benign (score 0.3352) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ile97Phe

c.289A>T · rs373579939 · VCV46232

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.3352	likely benign
REVEL	0.759	pathogenic-leaning
SaProt	LLR -8.23	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.99, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	24.5	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 0.005% European (non-Finnish) · 59/1,180,028 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00372% 60/1,613,320 alleles · very rare exomes 54/1,461,138 · genomes 6/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.005%	20,000
Remaining individualsnot grpmax-eligible	0.0016%	62,446

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.Ile97Phe
Coding: c.289A>T
MANE Select: NM_030662
dbSNP: rs373579939
Type: single nucleotide variant
Location: chr19:4117433 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 97: the protein kinase domain; a β-strand

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

Similar variants

MAP2K2 p.Ile97Met Conflicting classifications of pathogenicity ★ ⚠ same residue
MAP2K2 p.Ile97= Likely benign ★ same residue
MAP2K2 p.Ile97del Uncertain significance ★★ same residue
MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
MAP2K2 p.Pro128Gln Pathogenic ★★★ same condition
MAP2K2 p.Tyr134Cys Likely pathogenic ★★★ same condition
MAP2K2 p.Tyr134His Pathogenic ★★★ 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-ile97phe (accessed [today's date]).

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