Is MAPK6 p.Arg655Lys (c.1964G>A) pathogenic?

MAPK6 p.Arg655Lys (c.1964G>A) is classified Uncertain significance in MAPK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: likely benign (0.0593); Rare (popmax 0.202%, mid).

How common is MAPK6 p.Arg655Lys (c.1964G>A) in the general population?

MAPK6 p.Arg655Lys (c.1964G>A) is rare (popmax 0.202%, mid) (gnomAD).

What do computational predictors say about MAPK6 p.Arg655Lys (c.1964G>A)?

AlphaMissense predicts likely benign (score 0.0593) — an in-silico prediction, not a clinical call.

MAPK6 p.Arg655Lys

c.1964G>A · rs148363441 · VCV2355331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0593 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.202%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0593	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -5.28	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 5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 6,229 bp · p 0.8 · regional, not allelic
Overall
CADD	19.37	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 0.202% Middle Eastern · 9/4,452 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0787%

Overall 0.012% 193/1,611,852 alleles · rare exomes 178/1,459,650 · genomes 15/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.202%	495
Remaining individualsnot grpmax-eligible	0.0321%	3,115
European (non-Finnish)	0.0128%	7,814
South Asian	0.00659%	15,164
Admixed American	0.005%	19,996
Finnishnot grpmax-eligible	0.00312%	32,008
African / African-American	0.00267%	37,436

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.Arg655Lys
Coding: c.1964G>A
MANE Select: NM_002748
dbSNP: rs148363441
Type: single nucleotide variant
Location: chr15:52064798 (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.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.Arg406Gln Uncertain significance ★ ⚠ same type
MAPK6 p.Arg406Trp Uncertain significance ★ ⚠ same type
MAPK6 p.Arg449Lys 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-arg655lys (accessed [today's date]).

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