Is MAP2K2 p.Glu328Lys (c.982G>A) pathogenic?

MAP2K2 p.Glu328Lys (c.982G>A) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely pathogenic (0.8296); Very rare (popmax 0.00268%, afr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Glu328Lys (c.982G>A)?

MAP2K2 p.Glu328Lys (c.982G>A) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Glu328Lys (c.982G>A) in the general population?

MAP2K2 p.Glu328Lys (c.982G>A) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Glu328Lys (c.982G>A)?

AlphaMissense predicts likely pathogenic (score 0.8296) — an in-silico prediction, not a clinical call.

MAP2K2 p.Glu328Lys

c.982G>A · VCV4705647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.8296	likely pathogenic
REVEL	0.69	pathogenic-leaning
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.66, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	28.9	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 0.00268% African / African-American · 2/74,626 alleles

Filtering AF 0.000445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000186% 3/1,610,694 alleles · very rare exomes 2/1,459,262 · genomes 1/151,432 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,313
South Asian	0.0011%	90,998

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.Glu328Lys
Coding: c.982G>A
MANE Select: NM_030662
Type: single nucleotide variant
Location: chr19:4097281 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 328: 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.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
MAP2K2 p.Arg281Gln 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-glu328lys (accessed [today's date]).

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