Is MAP3K9 p.Pro371Ala (c.1111C>G) pathogenic?

MAP3K9 p.Pro371Ala (c.1111C>G) is classified Uncertain significance in MAP3K9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely pathogenic (0.9436); Very rare (popmax 0.005%, amr).

How common is MAP3K9 p.Pro371Ala (c.1111C>G) in the general population?

MAP3K9 p.Pro371Ala (c.1111C>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about MAP3K9 p.Pro371Ala (c.1111C>G)?

AlphaMissense predicts likely pathogenic (score 0.9436) — an in-silico prediction, not a clinical call.

MAP3K9 p.Pro371Ala

c.1111C>G · VCV4549532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9436 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9436	likely pathogenic
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -14.54	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 52 kb · p 9.3e-09 · regional, not allelic
Overall
CADD	29.1	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 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,614,178 alleles · very rare exomes 4/1,461,872 · genomes 0/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
European (non-Finnish)	8.47e-05%	1,180,034

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: MAP3K9
Protein: p.Pro371Ala
Coding: c.1111C>G
MANE Select: NM_001284230
Type: single nucleotide variant
Location: chr14:70749972 (GRCh38)
Gene constraint: LOEUF 0.674 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.56 · 2 PDB
Residue 371: the protein kinase domain; an α-helix

Full MAP3K9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K9 c.2027-415G>T Uncertain significance ★ same type
MAP3K9 p.Ala1086Ser Uncertain significance ★ ⚠ same type
MAP3K9 p.Ala116Gly Uncertain significance ★ ⚠ same type
MAP3K9 p.Ala246Thr Uncertain significance ★ ⚠ same type
MAP3K9 p.Ala309Val Uncertain significance ★ same type
MAP3K9 p.Ala379Thr Uncertain significance ★ ⚠ same type
MAP3K9 p.Ala65Ser Uncertain significance ★ ⚠ same type
MAP3K9 p.Ala787Val 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/map3k9-p-pro371ala (accessed [today's date]).

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