Is MAP2K2 p.Pro298Leu (c.893C>T) pathogenic?

MAP2K2 p.Pro298Leu (c.893C>T) is classified Benign in MAP2K2 (ClinVar, Expert panel, 10 submitters; last evaluated 2017-05-09). AlphaMissense: likely benign (0.0802); Rare (popmax 0.681%, eas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Pro298Leu (c.893C>T)?

MAP2K2 p.Pro298Leu (c.893C>T) is associated with RASopathy, hypertrophic cardiomyopathy, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is MAP2K2 p.Pro298Leu (c.893C>T) in the general population?

MAP2K2 p.Pro298Leu (c.893C>T) is rare (popmax 0.681%, eas) (gnomAD).

What do computational predictors say about MAP2K2 p.Pro298Leu (c.893C>T)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

MAP2K2 p.Pro298Leu

c.893C>T · rs200371894 · VCV40832

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.681%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.893C>T (p.Pro298Leu) variant in the MAP2K2 gene is 0.953% (68/5776) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.561	indeterminate
SaProt	LLR -9.01	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 8.6	GERP 0.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	23.8	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 0.681% East Asian · 303/44,482 alleles

Filtering AF 0.618% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.593%

Overall 0.0317% 508/1,603,844 alleles · rare exomes 434/1,451,514 · genomes 74/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.681%	147
Remaining individualsnot grpmax-eligible	0.0854%	1,171
South Asian	0.0434%	2,305
Admixed American	0.0102%	9,782
European (non-Finnish)	0.00901%	11,093
African / African-American	0.00133%	74,952

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.Pro298Leu
Coding: c.893C>T
MANE Select: NM_030662
dbSNP: rs200371894
Type: single nucleotide variant
Location: chr19:4099227 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 298: the protein kinase domain; the 'disordered' region

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: hypertrophic cardiomyopathy Noonan syndrome and Noonan-related syndrome

Similar variants

MAP2K2 p.Pro298= 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
MAP2K2 p.Arg231His Uncertain significance ★★★ ⚠ same condition
MAP2K2 p.Arg231Leu 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-pro298leu (accessed [today's date]).

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