Is MAP2K2 p.Gly65Ser (c.193G>A) pathogenic?

MAP2K2 p.Gly65Ser (c.193G>A) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.4236); Very rare (popmax 0.00445%, eas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Gly65Ser (c.193G>A)?

MAP2K2 p.Gly65Ser (c.193G>A) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Gly65Ser (c.193G>A) in the general population?

MAP2K2 p.Gly65Ser (c.193G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about MAP2K2 p.Gly65Ser (c.193G>A)?

AlphaMissense predicts ambiguous (score 0.4236) — an in-silico prediction, not a clinical call.

MAP2K2 p.Gly65Ser

c.193G>A · rs774875456 · VCV2202271

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4236 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.4236	ambiguous
REVEL	0.751	pathogenic-leaning
SaProt	LLR -13.52	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP -0.68, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	31.0	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 0.00445% East Asian · 2/44,898 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000186% 3/1,614,034 alleles · very rare exomes 2/1,461,826 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,449
Admixed American	0.00167%	60,008

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.Gly65Ser
Coding: c.193G>A
MANE Select: NM_030662
dbSNP: rs774875456
Type: single nucleotide variant
Location: chr19:4117529 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB

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.Gly65Asp Uncertain significance ★ ⚠ same residue
MAP2K2 p.Gly65= 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-gly65ser (accessed [today's date]).

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