Is MAPK6 p.Arg406Gln (c.1217G>A) pathogenic?

MAPK6 p.Arg406Gln (c.1217G>A) is classified Uncertain significance in MAPK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.1083); Ultra-rare (popmax 0.0134%, eas).

How common is MAPK6 p.Arg406Gln (c.1217G>A) in the general population?

MAPK6 p.Arg406Gln (c.1217G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about MAPK6 p.Arg406Gln (c.1217G>A)?

AlphaMissense predicts likely benign (score 0.1083) — an in-silico prediction, not a clinical call.

MAPK6 p.Arg406Gln

c.1217G>A · rs755817710 · VCV2356772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1083 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1083	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -6.00	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 8.6	GERP 3.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,229 bp · p 0.8 · regional, not allelic
Overall
CADD	22.5	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 0.0134% East Asian · 6/44,874 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00229% 37/1,613,614 alleles · ultra-rare exomes 35/1,461,426 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,479
Remaining individualsnot grpmax-eligible	0.0112%	8,923
South Asian	0.00879%	11,380
African / African-American	0.004%	24,973
Admixed American	0.00167%	59,970
European (non-Finnish)	0.00102%	98,314

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: MAPK6
Protein: p.Arg406Gln
Coding: c.1217G>A
MANE Select: NM_002748
dbSNP: rs755817710
Type: single nucleotide variant
Location: chr15:52064051 (GRCh38)
Gene constraint: LOEUF 0.465 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.61 · 4 PDB

Full MAPK6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK6 p.Arg406Trp Uncertain significance ★ ⚠ same residue
MAPK6 p.Ala218Gly Uncertain significance ★ ⚠ same type
MAPK6 p.Ala515Gly Uncertain significance ★ ⚠ same type
MAPK6 p.Ala515Ser Uncertain significance ★ ⚠ same type
MAPK6 p.Ala695Thr Uncertain significance ★ ⚠ same type
MAPK6 p.Arg256His Uncertain significance ★ ⚠ same type
MAPK6 p.Arg449Lys Uncertain significance ★ ⚠ same type
MAPK6 p.Arg635Lys 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/mapk6-p-arg406gln (accessed [today's date]).

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