Is MAP2K1 p.Arg181Lys (c.542G>A) pathogenic?

MAP2K1 p.Arg181Lys (c.542G>A) is classified Uncertain significance in MAP2K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely pathogenic (0.8521); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with MAP2K1 p.Arg181Lys (c.542G>A)?

MAP2K1 p.Arg181Lys (c.542G>A) is associated with RASopathy (ClinVar).

How common is MAP2K1 p.Arg181Lys (c.542G>A) in the general population?

MAP2K1 p.Arg181Lys (c.542G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K1 p.Arg181Lys (c.542G>A)?

AlphaMissense predicts likely pathogenic (score 0.8521) — an in-silico prediction, not a clinical call.

MAP2K1 p.Arg181Lys

c.542G>A · VCV4710024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8521 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.8521	likely pathogenic
REVEL	0.277	benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 94 kb · p 1.7e-15 · regional, not allelic
Overall
CADD	25.5	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

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: MAP2K1
Protein: p.Arg181Lys
Coding: c.542G>A
MANE Select: NM_002755
Type: single nucleotide variant
Location: chr15:66444681 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 181: the protein kinase domain; an α-helix

Full MAP2K1 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

MAP2K1 p.Arg181Met Uncertain significance ★ ⚠ same residue
MAP2K1 p.Arg108Leu Likely pathogenic ★★★ same condition
MAP2K1 p.Asn122Asp Pathogenic ★★★ ⚠ same condition
MAP2K1 p.Asp67Asn Pathogenic ★★★ same condition
MAP2K1 p.Glu203Gly Pathogenic ★★★ same condition
MAP2K1 p.Leu42Arg Likely pathogenic ★★★ same condition
MAP2K1 p.Leu42Phe Pathogenic ★★★ same condition
MAP2K1 p.Leu92Arg Pathogenic ★★★ 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/map2k1-p-arg181lys (accessed [today's date]).

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