Is MAPKAPK3 p.Pro169Ala (c.505C>G) pathogenic?

MAPKAPK3 p.Pro169Ala (c.505C>G) is classified Uncertain significance in MAPKAPK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-15). AlphaMissense: likely pathogenic (0.9392); Very rare (popmax 8.47e-05%, nfe).

How common is MAPKAPK3 p.Pro169Ala (c.505C>G) in the general population?

MAPKAPK3 p.Pro169Ala (c.505C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MAPKAPK3 p.Pro169Ala (c.505C>G)?

AlphaMissense predicts likely pathogenic (score 0.9392) — an in-silico prediction, not a clinical call.

MAPKAPK3 p.Pro169Ala

c.505C>G · VCV3608118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9392 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9392	likely pathogenic
REVEL	0.561	indeterminate
SaProt	LLR -12.03	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 2,164 bp · p 0.38 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,179,958 alleles

Overall 6.2e-05% 1/1,613,938 alleles · very rare exomes 0/1,461,762 · genomes 1/152,176 · joint denominator

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: MAPKAPK3
Protein: p.Pro169Ala
Coding: c.505C>G
MANE Select: NM_001243925
Type: single nucleotide variant
Location: chr3:50644409 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.10 · 5 PDB
Residue 169: the protein kinase domain; an α-helix

Full MAPKAPK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPKAPK3 p.Ala181Ser Uncertain significance ★★ ⚠ same type
MAPKAPK3 p.Arg112His Uncertain significance ★★ ⚠ same type
MAPKAPK3 p.Arg148Gln Uncertain significance ★★ ⚠ same type
MAPKAPK3 p.Arg148Trp Uncertain significance ★★ ⚠ same type
MAPKAPK3 p.Arg259Cys Uncertain significance ★★ same type
MAPKAPK3 p.Arg282Cys Uncertain significance ★★ ⚠ same type
MAPKAPK3 p.Arg282His Uncertain significance ★★ ⚠ same type
MAPKAPK3 p.Arg319Gln 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/mapkapk3-p-pro169ala (accessed [today's date]).

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