Is MAP2K6 p.Ala189Asp (c.566C>A) pathogenic?

MAP2K6 p.Ala189Asp (c.566C>A) is classified Uncertain significance in MAP2K6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1916); Absent from gnomAD v4.1.

How common is MAP2K6 p.Ala189Asp (c.566C>A) in the general population?

MAP2K6 p.Ala189Asp (c.566C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K6 p.Ala189Asp (c.566C>A)?

AlphaMissense predicts likely benign (score 0.1916) — an in-silico prediction, not a clinical call.

MAP2K6 p.Ala189Asp

c.566C>A · VCV4103152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1916 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1916	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.52, phastCons 0.27
Regional constraint	o/e 0.52	unconstrained · MANE · 109 kb · p 5.9e-14 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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: MAP2K6
Protein: p.Ala189Asp
Coding: c.566C>A
MANE Select: NM_002758
Type: single nucleotide variant
Location: chr17:69523544 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.58 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 9 PDB
Residue 189: the protein kinase domain

Full MAP2K6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K6 p.Arg254Gln Uncertain significance ★ ⚠ same type
MAP2K6 p.Glu167Ala Uncertain significance ★ ⚠ same type
MAP2K6 p.Gly147Val Uncertain significance ★ ⚠ same type
MAP2K6 p.Ile144Val Uncertain significance ★ ⚠ same type
MAP2K6 p.Ile39Val Uncertain significance ★ ⚠ same type
MAP2K6 p.Ile56Val Uncertain significance ★ ⚠ same type
MAP2K6 p.Leu186Val Uncertain significance ★ ⚠ same type
MAP2K6 p.Leu190Ile Uncertain significance ★ ⚠ same type

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/map2k6-p-ala189asp (accessed [today's date]).

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