Is EXOSC9 p.Arg133Pro (c.398G>C) pathogenic?

EXOSC9 p.Arg133Pro (c.398G>C) is classified Uncertain significance in EXOSC9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-14). AlphaMissense: likely pathogenic (0.9972); Very rare (popmax 0.00609%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXOSC9 p.Arg133Pro (c.398G>C)?

EXOSC9 p.Arg133Pro (c.398G>C) is associated with Inborn genetic diseases (ClinVar).

How common is EXOSC9 p.Arg133Pro (c.398G>C) in the general population?

EXOSC9 p.Arg133Pro (c.398G>C) is very rare (popmax 0.00609%, nfe) (gnomAD).

What do computational predictors say about EXOSC9 p.Arg133Pro (c.398G>C)?

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

EXOSC9 p.Arg133Pro

c.398G>C · rs201693852 · VCV1423713

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00609%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic · top 1% in EXOSC9
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -16.68	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 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	33.0	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 0.00609% European (non-Finnish) · 71/1,165,522 alleles

Filtering AF 0.00492% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00452%

Overall 0.0047% 75/1,596,416 alleles · very rare exomes 67/1,444,258 · genomes 8/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00609%	16,416
Admixed American	0.00502%	19,906
Remaining individualsnot grpmax-eligible	0.00162%	61,870

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: EXOSC9
Protein: p.Arg133Pro
Coding: c.398G>C
MANE Select: NM_005033
dbSNP: rs201693852
Type: single nucleotide variant
Location: chr4:121804635 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 8 PDB
Residue 133: the 'are binding' region; a β-strand

Full EXOSC9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EXOSC9 p.Arg133His Uncertain significance ★★ same residue
EXOSC9 p.Arg133Cys Uncertain significance ★ ⚠ same residue
EXOSC9 p.Ala148Val Uncertain significance ★★ ⚠ same condition
EXOSC9 p.Ala387Gly Uncertain significance ★★ ⚠ same condition
EXOSC9 p.Arg111Ser Uncertain significance ★★ ⚠ same condition
EXOSC9 p.Arg161Gln Uncertain significance ★★ ⚠ same condition
EXOSC9 p.Arg180Cys Uncertain significance ★★ same condition
EXOSC9 p.Arg180His Uncertain significance ★★ same condition

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/exosc9-p-arg133pro (accessed [today's date]).

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