Is MAP2K2 p.Ser295= (c.885G>A) pathogenic?

MAP2K2 p.Ser295= (c.885G>A) is classified Likely benign in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). Very rare (popmax 0.00679%, amr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ser295= (c.885G>A)?

MAP2K2 p.Ser295= (c.885G>A) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ser295= (c.885G>A) in the general population?

MAP2K2 p.Ser295= (c.885G>A) is very rare (popmax 0.00679%, amr) (gnomAD).

MAP2K2 p.Ser295=

c.885G>A · rs368405565 · VCV1158395

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00679%, amr)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -3.9
Overall
CADD	0.229	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00679% Admixed American · 4/58,876 alleles

Filtering AF 0.00229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.000498% 8/1,605,216 alleles · very rare exomes 8/1,452,882 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00679%	14,719
South Asian	0.00111%	89,972
European (non-Finnish)	0.000255%	392,163

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.Ser295=
Coding: c.885G>A
MANE Select: NM_030662
dbSNP: rs368405565
Type: single nucleotide variant
Location: chr19:4099235 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 295: the protein kinase domain; a modified residue (phosphoserine); the 'disordered' region

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.Ser295Leu Conflicting classifications of pathogenicity ★ ⚠ 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-ser295 (accessed [today's date]).

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