Is MAP2K2 p.Gln60His (c.180G>C) pathogenic?

MAP2K2 p.Gln60His (c.180G>C) is classified Likely pathogenic in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-20). AlphaMissense: likely pathogenic (0.729); Absent from gnomAD v4.1; Associated with cardiofaciocutaneous syndrome 4.

What condition is associated with MAP2K2 p.Gln60His (c.180G>C)?

MAP2K2 p.Gln60His (c.180G>C) is associated with cardiofaciocutaneous syndrome 4 (ClinVar).

How common is MAP2K2 p.Gln60His (c.180G>C) in the general population?

MAP2K2 p.Gln60His (c.180G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K2 p.Gln60His (c.180G>C)?

AlphaMissense predicts likely pathogenic (score 0.729) — an in-silico prediction, not a clinical call.

MAP2K2 p.Gln60His

c.180G>C · VCV4294094

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.729 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiofaciocutaneous syndrome 4

Computational evidence

Protein change
AlphaMissense	0.729	likely pathogenic ✓ concordant with ClinVar
REVEL	0.748	pathogenic-leaning
SaProt	LLR -11.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1	GERP -0.72, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	23.5	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: MAP2K2
Protein: p.Gln60His
Coding: c.180G>C
MANE Select: NM_030662
Type: single nucleotide variant
Location: chr19:4117542 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB

Full MAP2K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiofaciocutaneous syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP2K2 p.Gln60Ter Uncertain significance ★ same residue
MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
MAP2K2 p.Phe57Val 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
MAP2K2 p.Arg231Leu 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-gln60his (accessed [today's date]).

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