Is MAP2K2 p.Pro166= (c.498C>G) pathogenic?

MAP2K2 p.Pro166= (c.498C>G) is classified Likely benign in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-12). Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with MAP2K2 p.Pro166= (c.498C>G)?

MAP2K2 p.Pro166= (c.498C>G) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Pro166= (c.498C>G) in the general population?

MAP2K2 p.Pro166= (c.498C>G) is absent from gnomAD v4.1 (gnomAD).

MAP2K2 p.Pro166=

c.498C>G · rs139404261 · VCV3228055

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.9
Overall
CADD	0.097	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAP2K2
Protein: p.Pro166=
Coding: c.498C>G
MANE Select: NM_030662
dbSNP: rs139404261
Type: single nucleotide variant
Location: chr19:4102406 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 166: 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.Pro166Leu Uncertain significance ★ ⚠ same residue
MAP2K2 p.Pro166Ser Uncertain significance ★ ⚠ 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-pro166 (accessed [today's date]).

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