Is MAP2K6 p.Arg254Gln (c.761G>A) pathogenic?

MAP2K6 p.Arg254Gln (c.761G>A) is classified Uncertain significance in MAP2K6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.0942); Rare (popmax 0.16%, afr).

How common is MAP2K6 p.Arg254Gln (c.761G>A) in the general population?

MAP2K6 p.Arg254Gln (c.761G>A) is rare (popmax 0.16%, afr) (gnomAD).

What do computational predictors say about MAP2K6 p.Arg254Gln (c.761G>A)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

MAP2K6 p.Arg254Gln

c.761G>A · rs146595343 · VCV2347057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.16%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -8.81	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 3,102 bp · p 1.8e-13 · regional, not allelic
Overall
CADD	31.0	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 0.16% African / African-American · 120/74,946 alleles

Filtering AF 0.137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.128%

Overall 0.0399% 643/1,613,426 alleles · rare exomes 548/1,461,396 · genomes 95/152,030 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.16%	625
Admixed American	0.0451%	2,219
European (non-Finnish)	0.0401%	2,494
Remaining individualsnot grpmax-eligible	0.0256%	3,905
Middle Eastern	0.0168%	5,954
Finnishnot grpmax-eligible	0.00939%	10,654

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.Arg254Gln
Coding: c.761G>A
MANE Select: NM_002758
dbSNP: rs146595343
Type: single nucleotide variant
Location: chr17:69526589 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.58 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 9 PDB
Residue 254: the protein kinase domain

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.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-arg254gln (accessed [today's date]).

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