Is EXOSC9 p.Phe90Ser (c.269T>C) pathogenic?

EXOSC9 p.Phe90Ser (c.269T>C) is classified Uncertain significance in EXOSC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-30). AlphaMissense: likely pathogenic (0.6769); Very rare (popmax 0.000169%, nfe).

How common is EXOSC9 p.Phe90Ser (c.269T>C) in the general population?

EXOSC9 p.Phe90Ser (c.269T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about EXOSC9 p.Phe90Ser (c.269T>C)?

AlphaMissense predicts likely pathogenic (score 0.6769) — an in-silico prediction, not a clinical call.

EXOSC9 p.Phe90Ser

c.269T>C · rs2476760841 · VCV2881785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6769	likely pathogenic
REVEL	0.66	pathogenic-leaning
SaProt	LLR -12.98	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	31.0	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 0.000169% European (non-Finnish) · 2/1,179,992 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,086 alleles · very rare exomes 2/1,461,754 · genomes 0/152,332 · 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: EXOSC9
Protein: p.Phe90Ser
Coding: c.269T>C
MANE Select: NM_005033
dbSNP: rs2476760841
Type: single nucleotide variant
Location: chr4:121802781 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 8 PDB
Residue 90: the 'are binding' region

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

Similar variants

EXOSC9 p.Phe90= Likely benign ★ same residue
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

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-phe90ser (accessed [today's date]).

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