Is MAPK9 p.His66Pro (c.197A>C) pathogenic?

MAPK9 p.His66Pro (c.197A>C) is classified Uncertain significance in MAPK9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.9972); Absent from gnomAD v4.1.

How common is MAPK9 p.His66Pro (c.197A>C) in the general population?

MAPK9 p.His66Pro (c.197A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPK9 p.His66Pro (c.197A>C)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

MAPK9 p.His66Pro

c.197A>C · VCV4103863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic
REVEL	0.583	indeterminate
SaProt	LLR -17.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 33 kb · p 6e-12 · regional, not allelic
Overall
CADD	28.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAPK9
Protein: p.His66Pro
Coding: c.197A>C
MANE Select: NM_002752
Type: single nucleotide variant
Location: chr5:180269335 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.71 · 5 PDB
Residue 66: the protein kinase domain; an α-helix

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

Similar variants

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.Arg25Cys Uncertain significance ★ ⚠ same type
MAPK9 p.Arg25His 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

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-his66pro (accessed [today's date]).

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