Is MAP2K2 p.Pro128Arg (c.383C>G) pathogenic?

MAP2K2 p.Pro128Arg (c.383C>G) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2014-04-07). AlphaMissense: likely pathogenic (0.9631); Absent from gnomAD v4.1.

How common is MAP2K2 p.Pro128Arg (c.383C>G) in the general population?

MAP2K2 p.Pro128Arg (c.383C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K2 p.Pro128Arg (c.383C>G)?

AlphaMissense predicts likely pathogenic (score 0.9631) — an in-silico prediction, not a clinical call.

MAP2K2 p.Pro128Arg

c.383C>G · rs267607230 · VCV40792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9631 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9631	likely pathogenic
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -14.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	27.0	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.Pro128Arg
Coding: c.383C>G
MANE Select: NM_030662
dbSNP: rs267607230
Type: single nucleotide variant
Location: chr19:4110576 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 128: the protein kinase domain; a UniProt-annotated variant site (in cfc4; results in increased kinase activity)

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

Similar variants

MAP2K2 p.Pro128Gln Pathogenic ★★★ same residue
MAP2K2 p.Pro128Leu Pathogenic/Likely pathogenic ★★ same residue
MAP2K2 p.Pro128= Likely benign ★★ same residue
MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same type
MAP2K2 p.Phe57Cys Pathogenic ★★★ same type
MAP2K2 p.Phe57Val Pathogenic ★★★ same type
MAP2K2 p.Tyr134Cys Likely pathogenic ★★★ same type
MAP2K2 p.Tyr134His Pathogenic ★★★ same type

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-pro128arg (accessed [today's date]).

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