Is MAPK9 p.Arg25Cys (c.73C>T) pathogenic?

MAPK9 p.Arg25Cys (c.73C>T) is classified Uncertain significance in MAPK9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.9624); Very rare (popmax 0.00891%, eas).

How common is MAPK9 p.Arg25Cys (c.73C>T) in the general population?

MAPK9 p.Arg25Cys (c.73C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about MAPK9 p.Arg25Cys (c.73C>T)?

AlphaMissense predicts likely pathogenic (score 0.9624) — an in-silico prediction, not a clinical call.

MAPK9 p.Arg25Cys

c.73C>T · VCV4051661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9624	likely pathogenic
REVEL	0.772	pathogenic-leaning
SaProt	LLR -12.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 96 bp · p 0.74 · regional, not allelic
Overall
CADD	28.6	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 0.00891% East Asian · 4/44,888 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00105% 17/1,614,014 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,222
South Asian	0.00439%	22,773
African / African-American	0.00401%	24,965
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000424%	236,006

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: MAPK9
Protein: p.Arg25Cys
Coding: c.73C>T
MANE Select: NM_002752
Type: single nucleotide variant
Location: chr5:180280489 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.71 · 5 PDB

Full MAPK9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK9 p.Arg25His Uncertain significance ★ ⚠ same residue
MAPK9 c.617-399G>A Uncertain significance ★ same type
MAPK9 p.Ala246Val Uncertain significance ★ ⚠ same type
MAPK9 p.Arg174Gly Uncertain significance ★ ⚠ same type
MAPK9 p.Arg424Pro Uncertain significance ★ ⚠ same type
MAPK9 p.Asn262Lys Uncertain significance ★ ⚠ same type
MAPK9 p.Asn394Ser Uncertain significance ★ ⚠ same type
MAPK9 p.Asp287Glu 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/mapk9-p-arg25cys (accessed [today's date]).

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