Is MAP2K2 p.Ala162fs (c.485_492del) pathogenic?

MAP2K2 p.Ala162fs (c.485492del) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). Very rare (popmax 8.49e-05%, nfe); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ala162fs (c.485_492del)?

MAP2K2 p.Ala162fs (c.485_492del) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ala162fs (c.485_492del) in the general population?

MAP2K2 p.Ala162fs (c.485_492del) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

MAP2K2 p.Ala162fs

c.485_492del · VCV3725673

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

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 4 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 1.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,534 alleles

Overall 6.22e-05% 1/1,606,836 alleles · very rare exomes 1/1,454,552 · genomes 0/152,284 · joint denominator

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.Ala162fs
Coding: c.485_492del
MANE Select: NM_030662
Type: Deletion
Location: chr19:4102412 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 162: the protein kinase domain; a β-strand

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.Ala162Val Uncertain significance ★★ 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.Ala162Thr Uncertain significance ★ ⚠ same residue
MAP2K2 p.Arg303fs 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-ala162fs (accessed [today's date]).

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