Is MAP2K2 p.Leu181fs (c.540del) pathogenic?

MAP2K2 p.Leu181fs (c.540del) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). Associated with RASopathy.

What condition is associated with MAP2K2 p.Leu181fs (c.540del)?

MAP2K2 p.Leu181fs (c.540del) is associated with RASopathy (ClinVar).

MAP2K2 p.Leu181fs

c.540del · VCV4710874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2	GERP -3.5, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: MAP2K2
Protein: p.Leu181fs
Coding: c.540del
MANE Select: NM_030662
Type: Deletion
Location: chr19:4101269 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 181: the protein kinase domain; an α-helix

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.Leu181Ser Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Leu181= Likely benign ★ same residue
MAP2K2 p.Leu54fs Uncertain significance ★★ same condition
MAP2K2 c.303+15del Benign/Likely benign ★★ same condition
MAP2K2 c.1046+5_1046+8del Uncertain significance ★ same condition
MAP2K2 c.1046+5del Uncertain significance ★ same condition
MAP2K2 c.578_580+9del Uncertain significance ★ same condition
MAP2K2 p.Ala162fs 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-leu181fs (accessed [today's date]).

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