Is MAP2K2 p.Asp151Glu (c.453C>G) pathogenic?

MAP2K2 p.Asp151Glu (c.453C>G) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-02-15). AlphaMissense: likely pathogenic (0.9233); Very rare (popmax 0.000426%, nfe); Associated with RASopathy.

What condition is associated with MAP2K2 p.Asp151Glu (c.453C>G)?

MAP2K2 p.Asp151Glu (c.453C>G) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Asp151Glu (c.453C>G) in the general population?

MAP2K2 p.Asp151Glu (c.453C>G) is very rare (popmax 0.000426%, nfe) (gnomAD).

What do computational predictors say about MAP2K2 p.Asp151Glu (c.453C>G)?

AlphaMissense predicts likely pathogenic (score 0.9233) — an in-silico prediction, not a clinical call.

MAP2K2 p.Asp151Glu

c.453C>G · rs17851657 · VCV543996

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9233 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000426%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9233	likely pathogenic
REVEL	0.559	indeterminate
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.54 · evaluated, not missing
Constraint at this position
Conservation	phyloP -7.2	GERP -3.5
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	12.92	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 0.000426% European (non-Finnish) · 5/1,172,814 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000313% 5/1,597,604 alleles · very rare exomes 5/1,445,374 · genomes 0/152,230 · 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.Asp151Glu
Coding: c.453C>G
MANE Select: NM_030662
dbSNP: rs17851657
Type: single nucleotide variant
Location: chr19:4102451 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 151: the protein kinase domain

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.Asp151= 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-asp151glu (accessed [today's date]).

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