Is MAPK6 p.Leu260Val (c.778C>G) pathogenic?

MAPK6 p.Leu260Val (c.778C>G) is classified Uncertain significance in MAPK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-26). AlphaMissense: likely benign (0.1329); Ultra-rare (popmax 0.0107%, afr).

How common is MAPK6 p.Leu260Val (c.778C>G) in the general population?

MAPK6 p.Leu260Val (c.778C>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about MAPK6 p.Leu260Val (c.778C>G)?

AlphaMissense predicts likely benign (score 0.1329) — an in-silico prediction, not a clinical call.

MAPK6 p.Leu260Val

c.778C>G · VCV3543157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1329 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1329	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -9.02	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 7.7	GERP 3.6, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 12 kb · p 3.5e-10 · regional, not allelic
Overall
CADD	25.3	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

Grpmax group 0.0107% African / African-American · 8/74,914 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00062% 10/1,613,496 alleles · ultra-rare exomes 2/1,461,304 · genomes 8/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,364
Admixed American	0.00167%	59,942
Remaining individualsnot grpmax-eligible	0.0016%	62,454

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.Leu260Val
Coding: c.778C>G
MANE Select: NM_002748
Type: single nucleotide variant
Location: chr15:52058710 (GRCh38)
Gene constraint: LOEUF 0.465 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.61 · 4 PDB
Residue 260: the protein kinase domain; an α-helix

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-leu260val (accessed [today's date]).

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