Is MAP2K2 p.Arg397Leu (c.1190G>T) pathogenic?

MAP2K2 p.Arg397Leu (c.1190G>T) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: likely benign (0.1688); Very rare (popmax 0.000261%, nfe); Associated with RASopathy.

What condition is associated with MAP2K2 p.Arg397Leu (c.1190G>T)?

MAP2K2 p.Arg397Leu (c.1190G>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Arg397Leu (c.1190G>T) in the general population?

MAP2K2 p.Arg397Leu (c.1190G>T) is very rare (popmax 0.000261%, nfe) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg397Leu (c.1190G>T)?

AlphaMissense predicts likely benign (score 0.1688) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg397Leu

c.1190G>T · rs751040819 · VCV2870053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1688 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000261%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.1688	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -3.2, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	22.5	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 0.000261% European (non-Finnish) · 3/1,147,478 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000193% 3/1,551,382 alleles · very rare exomes 3/1,399,042 · genomes 0/152,340 · 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.Arg397Leu
Coding: c.1190G>T
MANE Select: NM_030662
dbSNP: rs751040819
Type: single nucleotide variant
Location: chr19:4090611 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB

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.Arg397His Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Arg397Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MAP2K2 p.Arg397= Likely benign 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-arg397leu (accessed [today's date]).

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