Is MAP3K9 p.Pro580Arg (c.1739C>G) pathogenic?

MAP3K9 p.Pro580Arg (c.1739C>G) is classified Uncertain significance in MAP3K9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1173); Very rare (popmax 0.000339%, nfe).

How common is MAP3K9 p.Pro580Arg (c.1739C>G) in the general population?

MAP3K9 p.Pro580Arg (c.1739C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about MAP3K9 p.Pro580Arg (c.1739C>G)?

AlphaMissense predicts likely benign (score 0.1173) — an in-silico prediction, not a clinical call.

MAP3K9 p.Pro580Arg

c.1739C>G · VCV4103460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1173 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1173	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -5.51	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 2.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 16 kb · p 0.049 · regional, not allelic
Overall
CADD	16.31	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 0.000339% European (non-Finnish) · 4/1,179,952 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,752 alleles · very rare exomes 3/1,461,728 · genomes 1/152,024 · 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: MAP3K9
Protein: p.Pro580Arg
Coding: c.1739C>G
MANE Select: NM_001284230
Type: single nucleotide variant
Location: chr14:70738350 (GRCh38)
Gene constraint: LOEUF 0.674 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.56 · 2 PDB
Residue 580: the 'disordered' region

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

Similar variants

MAP3K9 p.Pro580Leu Uncertain significance ★ ⚠ same residue
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

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-pro580arg (accessed [today's date]).

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