Is MAP2K2 p.Ala355Pro (c.1063G>C) pathogenic?

MAP2K2 p.Ala355Pro (c.1063G>C) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.5701); Very rare (popmax 0.000346%, nfe); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ala355Pro (c.1063G>C)?

MAP2K2 p.Ala355Pro (c.1063G>C) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ala355Pro (c.1063G>C) in the general population?

MAP2K2 p.Ala355Pro (c.1063G>C) is very rare (popmax 0.000346%, nfe) (gnomAD).

What do computational predictors say about MAP2K2 p.Ala355Pro (c.1063G>C)?

AlphaMissense predicts likely pathogenic (score 0.5701) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ala355Pro

c.1063G>C · rs776743002 · VCV2585789

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000346%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.5701	likely pathogenic
REVEL	0.206	benign-leaning
SaProt	LLR -10.54	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	26.1	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 0.000346% European (non-Finnish) · 4/1,156,730 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000255% 4/1,569,804 alleles · very rare exomes 4/1,417,496 · genomes 0/152,308 · 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.Ala355Pro
Coding: c.1063G>C
MANE Select: NM_030662
dbSNP: rs776743002
Type: single nucleotide variant
Location: chr19:4094482 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 355: the protein kinase domain; a turn

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.Ala355Val Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Ala355= Benign/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

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-ala355pro (accessed [today's date]).

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