Is MAP2K2 p.Pro282Ser (c.844C>T) pathogenic?

MAP2K2 p.Pro282Ser (c.844C>T) is classified Benign in MAP2K2 (ClinVar, Expert panel, 9 submitters; last evaluated 2024-12-03). AlphaMissense: likely benign (0.0752); Rare (popmax 0.165%, afr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Pro282Ser (c.844C>T)?

MAP2K2 p.Pro282Ser (c.844C>T) is associated with RASopathy, Noonan syndrome (ClinVar).

How common is MAP2K2 p.Pro282Ser (c.844C>T) in the general population?

MAP2K2 p.Pro282Ser (c.844C>T) is rare (popmax 0.165%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Pro282Ser (c.844C>T)?

AlphaMissense predicts likely benign (score 0.0752) — an in-silico prediction, not a clinical call.

MAP2K2 p.Pro282Ser

c.844C>T · rs142307980 · VCV40826

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0752 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BP5 BP4 BA1

Curation rationale (ClinGen, verbatim)

The c.844C>T variant in the MAP2K2 gene is a missense variant predicted to cause substitution of proline by serine at amino acid 282 (p.Pro282Ser). The filtering allele frequency in gnomAD v2.1.1 is 0.001415 (42/22756 alleles) in the African/African American population, meeting the criterion for BA1. The computational predictor REVEL gives a score of 0.072, which predicts no impact on protein function (BP4). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data; GTR ID's 26957; SCV000207963.8). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5 (Specification Version 2.3, 12/3/2024)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0752	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.43, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	18.44	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 0.165% African / African-American · 124/74,958 alleles

Filtering AF 0.142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.133%

Overall 0.0116% 187/1,606,046 alleles · rare exomes 86/1,453,692 · genomes 101/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.165%	604
Admixed American	0.0695%	1,438
Middle Eastern	0.0331%	3,022
Remaining individualsnot grpmax-eligible	0.0193%	5,181
European (non-Finnish)	0.00068%	147,098

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.Pro282Ser
Coding: c.844C>T
MANE Select: NM_030662
dbSNP: rs142307980
Type: single nucleotide variant
Location: chr19:4099276 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 282: 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

Also linked: Noonan syndrome

Similar variants

MAP2K2 p.Pro282= 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-pro282ser (accessed [today's date]).

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