Is EXOSC9 p.Pro92Ser (c.274C>T) pathogenic?

EXOSC9 p.Pro92Ser (c.274C>T) is classified Uncertain significance in EXOSC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: likely benign (0.0726); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with EXOSC9 p.Pro92Ser (c.274C>T)?

EXOSC9 p.Pro92Ser (c.274C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXOSC9 p.Pro92Ser (c.274C>T) in the general population?

EXOSC9 p.Pro92Ser (c.274C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about EXOSC9 p.Pro92Ser (c.274C>T)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

EXOSC9 p.Pro92Ser

c.274C>T · rs944611694 · VCV2293949

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -8.52	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	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	21.6	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 0.00167% Admixed American · 1/59,928 alleles

Overall 0.000186% 3/1,613,828 alleles · very rare exomes 2/1,461,658 · genomes 1/152,170 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,928
African / African-American	0.00134%	74,886
European (non-Finnish)	8.47e-05%	1,179,970

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.Pro92Ser
Coding: c.274C>T
MANE Select: NM_005033
dbSNP: rs944611694
Type: single nucleotide variant
Location: chr4:121802786 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 8 PDB
Residue 92: the 'are binding' region; a turn

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.Ala148Val Uncertain significance ★★ ⚠ same condition
EXOSC9 p.Ala387Gly Uncertain significance ★★ ⚠ same condition
EXOSC9 p.Arg111Ser Uncertain significance ★★ ⚠ same condition
EXOSC9 p.Arg133His Uncertain significance ★★ same condition
EXOSC9 p.Arg133Pro 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-pro92ser (accessed [today's date]).

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