Is MAPK9 p.Ile396Val (c.1186A>G) pathogenic?

MAPK9 p.Ile396Val (c.1186A>G) is classified Uncertain significance in MAPK9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). AlphaMissense: likely benign (0.0961); Very rare (popmax 0.00195%, nfe).

How common is MAPK9 p.Ile396Val (c.1186A>G) in the general population?

MAPK9 p.Ile396Val (c.1186A>G) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about MAPK9 p.Ile396Val (c.1186A>G)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

MAPK9 p.Ile396Val

c.1186A>G · VCV4051664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -5.82	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 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 11 kb · p 0.00097 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00195% European (non-Finnish) · 23/1,179,978 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00143% 23/1,613,968 alleles · very rare exomes 22/1,461,776 · genomes 1/152,192 · 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: MAPK9
Protein: p.Ile396Val
Coding: c.1186A>G
MANE Select: NM_002752
Type: single nucleotide variant
Location: chr5:180236473 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.71 · 5 PDB
Residue 396: the 'disordered' region

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-ile396val (accessed [today's date]).

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