Is EXOSC9 p.Ser353Pro (c.1057T>C) pathogenic?

EXOSC9 p.Ser353Pro (c.1057T>C) is classified Uncertain significance in EXOSC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-29). AlphaMissense: likely benign (0.1092); Very rare (popmax 0.000254%, nfe).

How common is EXOSC9 p.Ser353Pro (c.1057T>C) in the general population?

EXOSC9 p.Ser353Pro (c.1057T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about EXOSC9 p.Ser353Pro (c.1057T>C)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

EXOSC9 p.Ser353Pro

c.1057T>C · rs778847636 · VCV2012214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -8.37	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 4.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	21.4	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 0.000254% European (non-Finnish) · 3/1,179,610 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,384 alleles · very rare

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.Ser353Pro
Coding: c.1057T>C
MANE Select: NM_005033
dbSNP: rs778847636
Type: single nucleotide variant
Location: chr4:121813948 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 8 PDB
Residue 353: a UniProt-annotated variant site (in pch1d; reduced exosc9 and exosome levels in patient cells); the 'disordered' region

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

Similar variants

EXOSC9 p.Arg161Ter Pathogenic/Likely pathogenic ★★ same type
EXOSC9 p.Arg212Ter Pathogenic ★★ same type
EXOSC9 p.Arg229Ter Pathogenic/Likely pathogenic ★★ same type
EXOSC9 p.Leu14Pro Pathogenic/Likely pathogenic ★★ same type
EXOSC9 p.Ser7Ter Pathogenic/Likely pathogenic ★★ same type
EXOSC9 c.1157-172A>G Uncertain significance ★★ same type
EXOSC9 p.Ala148Val Uncertain significance ★★ ⚠ same type
EXOSC9 p.Ala387Gly 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/exosc9-p-ser353pro (accessed [today's date]).

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