Is MAP2K2 p.Leu181Ser (c.542T>C) pathogenic?

MAP2K2 p.Leu181Ser (c.542T>C) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-11). AlphaMissense: likely pathogenic (0.9982); No allele count reported in gnomAD v4.1 (AN 1,582,820); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Leu181Ser (c.542T>C)?

MAP2K2 p.Leu181Ser (c.542T>C) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is MAP2K2 p.Leu181Ser (c.542T>C) in the general population?

MAP2K2 p.Leu181Ser (c.542T>C) is no allele count reported in gnomAD v4.1 (AN 1,582,820) (gnomAD).

What do computational predictors say about MAP2K2 p.Leu181Ser (c.542T>C)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

MAP2K2 p.Leu181Ser

c.542T>C · rs2512310635 · VCV2129638

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,582,820)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic · top 8% in MAP2K2
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -15.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,582,820). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MAP2K2
Protein: p.Leu181Ser
Coding: c.542T>C
MANE Select: NM_030662
dbSNP: rs2512310635
Type: single nucleotide variant
Location: chr19:4101267 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RASopathy

Similar variants

MAP2K2 p.Leu181= Likely benign ★ same residue
MAP2K2 p.Leu181fs Uncertain significance ★ same residue
MAP2K2 p.Leu181Met 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

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-leu181ser (accessed [today's date]).

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