Is MAP2K2 p.Ala56Asp (c.167C>A) pathogenic?

MAP2K2 p.Ala56Asp (c.167C>A) is classified Likely pathogenic in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: ambiguous (0.403); Absent from gnomAD v4.1; Associated with cardiofaciocutaneous syndrome 4.

What condition is associated with MAP2K2 p.Ala56Asp (c.167C>A)?

MAP2K2 p.Ala56Asp (c.167C>A) is associated with cardiofaciocutaneous syndrome 4 (ClinVar).

How common is MAP2K2 p.Ala56Asp (c.167C>A) in the general population?

MAP2K2 p.Ala56Asp (c.167C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K2 p.Ala56Asp (c.167C>A)?

AlphaMissense predicts ambiguous (score 0.403) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ala56Asp

c.167C>A · rs2145080530 · VCV2444198

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.403 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

cardiofaciocutaneous syndrome 4

Computational evidence

Protein change
AlphaMissense	0.403	ambiguous
REVEL	0.703	pathogenic-leaning
SaProt	LLR -8.93	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	28.7	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.Ala56Asp
Coding: c.167C>A
MANE Select: NM_030662
dbSNP: rs2145080530
Type: single nucleotide variant
Location: chr19:4117555 (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.Ala56Thr Uncertain significance ★ ⚠ same residue
MAP2K2 p.Ala56= Likely benign ★ 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

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-ala56asp (accessed [today's date]).

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