Is MAP2K6 p.Thr28Ala (c.82A>G) pathogenic?

MAP2K6 p.Thr28Ala (c.82A>G) is classified Uncertain significance in MAP2K6 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-03-22). AlphaMissense: likely benign (0.0678); Very rare (popmax 0.00892%, eas).

How common is MAP2K6 p.Thr28Ala (c.82A>G) in the general population?

MAP2K6 p.Thr28Ala (c.82A>G) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about MAP2K6 p.Thr28Ala (c.82A>G)?

AlphaMissense predicts likely benign (score 0.0678) — an in-silico prediction, not a clinical call.

MAP2K6 p.Thr28Ala

c.82A>G · rs529602401 · VCV2528375

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0678	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -5.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 2.5, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 109 kb · p 5.9e-14 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.00892% East Asian · 4/44,866 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000372% 6/1,613,144 alleles · very rare exomes 5/1,460,796 · genomes 1/152,348 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,216
Remaining individualsnot grpmax-eligible	0.0016%	62,428
South Asian	0.0011%	91,042

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: MAP2K6
Protein: p.Thr28Ala
Coding: c.82A>G
MANE Select: NM_002758
dbSNP: rs529602401
Type: single nucleotide variant
Location: chr17:69505845 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.58 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 9 PDB
Residue 28: the 'disordered' region

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

Similar variants

MAP2K6 p.Ala189Asp Uncertain significance ★ ⚠ same type
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

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-thr28ala (accessed [today's date]).

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