Is MAPK3 p.Arg309Gln (c.926G>A) pathogenic?

MAPK3 p.Arg309Gln (c.926G>A) is classified Uncertain significance in MAPK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). AlphaMissense: likely benign (0.0892); Ultra-rare (popmax 0.0331%, mid).

How common is MAPK3 p.Arg309Gln (c.926G>A) in the general population?

MAPK3 p.Arg309Gln (c.926G>A) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about MAPK3 p.Arg309Gln (c.926G>A)?

AlphaMissense predicts likely benign (score 0.0892) — an in-silico prediction, not a clinical call.

MAPK3 p.Arg309Gln

c.926G>A · VCV4103784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0892 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0892	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.86, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 604 bp · p 0.042 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0331% Middle Eastern · 2/6,050 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00249% 40/1,606,972 alleles · ultra-rare exomes 37/1,454,842 · genomes 3/152,130 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,025
East Asian	0.00669%	14,943
Remaining individualsnot grpmax-eligible	0.00643%	15,545
Admixed American	0.00504%	19,847
South Asian	0.00334%	29,969
European (non-Finnish)	0.00213%	47,040

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: MAPK3
Protein: p.Arg309Gln
Coding: c.926G>A
MANE Select: NM_002746
Type: single nucleotide variant
Location: chr16:30116985 (GRCh38)
Gene constraint: LOEUF 0.935 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.09 · 8 PDB
Residue 309: the protein kinase domain; an α-helix

Full MAPK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK3 p.Arg309Gly Uncertain significance ★ ⚠ same residue
MAPK3 p.Gly11= Likely benign ★★ same type
MAPK3 p.Pro336= Benign/Likely benign ★★ same type
MAPK3 p.Tyr148Cys Likely pathogenic ★ same type
MAPK3 p.Ala378Asp Uncertain significance ★ ⚠ same type
MAPK3 p.Arg15Ser Uncertain significance ★ ⚠ same type
MAPK3 p.Arg242Gln Uncertain significance ★ ⚠ same type
MAPK3 p.Arg370Cys 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/mapk3-p-arg309gln (accessed [today's date]).

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