Is MAPKAPK3 p.Pro28Ala (c.82C>G) pathogenic?

MAPKAPK3 p.Pro28Ala (c.82C>G) is classified Conflicting classifications of pathogenicity in MAPKAPK3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-02). AlphaMissense: likely benign (0.0487); Rare (popmax 0.408%, eas); Associated with patterned macular dystrophy 3.

What condition is associated with MAPKAPK3 p.Pro28Ala (c.82C>G)?

MAPKAPK3 p.Pro28Ala (c.82C>G) is associated with patterned macular dystrophy 3 (ClinVar).

How common is MAPKAPK3 p.Pro28Ala (c.82C>G) in the general population?

MAPKAPK3 p.Pro28Ala (c.82C>G) is rare (popmax 0.408%, eas) (gnomAD).

What do computational predictors say about MAPKAPK3 p.Pro28Ala (c.82C>G)?

AlphaMissense predicts likely benign (score 0.0487) — an in-silico prediction, not a clinical call.

MAPKAPK3 p.Pro28Ala

Q: How is Martinique crinkled retinal pigment epitheliopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.82C>G · rs375412266 · VCV1587693

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0487 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.408%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

patterned macular dystrophy 3

Computational evidence

Protein change
AlphaMissense	0.0487	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -5.86	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 0.89	GERP 0.41, phastCons 0.3
Regional constraint	o/e 1.04	unconstrained · MANE · 23 kb · p 0.63 · regional, not allelic
Overall
CADD	15.7	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 0.408% East Asian · 183/44,848 alleles

Filtering AF 0.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.341%

Overall 0.0115% 186/1,610,458 alleles · rare exomes 178/1,458,168 · genomes 8/152,290 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.408%	245
Remaining individualsnot grpmax-eligible	0.0016%	62,338
South Asian	0.0011%	91,042
European (non-Finnish)	8.49e-05%	1,177,662

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.Pro28Ala
Coding: c.82C>G
MANE Select: NM_001243925
dbSNP: rs375412266
Type: single nucleotide variant
Location: chr3:50617647 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.10 · 5 PDB
Residue 28: a UniProt-annotated variant site (in a glioblastoma multiforme sample; somatic mutation); the 'disordered' region

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

Disease context

patterned macular dystrophy 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Martinique crinkled retinal pigment epitheliopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MAPKAPK3 p.Pro28Arg Uncertain significance ★★ ⚠ same residue
MAPKAPK3 p.Pro28Leu Uncertain significance ★ ⚠ same residue
MAPKAPK3 p.Asn300Lys Uncertain significance ★ ⚠ same condition
MAPKAPK3 p.Leu173Pro Pathogenic same condition
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

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-pro28ala (accessed [today's date]).

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