Is MAP2K2 p.Arg92Gly (c.274A>G) pathogenic?

MAP2K2 p.Arg92Gly (c.274A>G) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.3021); Ultra-rare (popmax 0.0233%, amr); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Arg92Gly (c.274A>G)?

MAP2K2 p.Arg92Gly (c.274A>G) is associated with Cardiovascular phenotype, neurofibromatosis-Noonan syndrome, RASopathy (ClinVar).

How common is MAP2K2 p.Arg92Gly (c.274A>G) in the general population?

MAP2K2 p.Arg92Gly (c.274A>G) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg92Gly (c.274A>G)?

AlphaMissense predicts likely benign (score 0.3021) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg92Gly

c.274A>G · rs759061964 · VCV40772

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.3021 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3021	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -9.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP -3.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	21.5	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 0.0233% Admixed American · 14/60,016 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.0026% 42/1,613,872 alleles · ultra-rare exomes 34/1,461,558 · genomes 8/152,314 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,287
Middle Eastern	0.0168%	5,940
Remaining individualsnot grpmax-eligible	0.0096%	10,416
African / African-American	0.004%	25,023
Finnishnot grpmax-eligible	0.00313%	31,926
European (non-Finnish)	0.00136%	73,752

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.Arg92Gly
Coding: c.274A>G
MANE Select: NM_030662
dbSNP: rs759061964
Type: single nucleotide variant
Location: chr19:4117448 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 92: the protein kinase domain; a turn

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurofibromatosis-Noonan syndrome RASopathy

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-arg92gly (accessed [today's date]).

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