Is EXOSC9 p.Val129Phe (c.385G>T) pathogenic?

EXOSC9 p.Val129Phe (c.385G>T) is classified Uncertain significance in EXOSC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-02). AlphaMissense: likely pathogenic (0.9777); Very rare (popmax 0.00512%, amr); Associated with Inborn genetic diseases.

What condition is associated with EXOSC9 p.Val129Phe (c.385G>T)?

EXOSC9 p.Val129Phe (c.385G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXOSC9 p.Val129Phe (c.385G>T) in the general population?

EXOSC9 p.Val129Phe (c.385G>T) is very rare (popmax 0.00512%, amr) (gnomAD).

What do computational predictors say about EXOSC9 p.Val129Phe (c.385G>T)?

AlphaMissense predicts likely pathogenic (score 0.9777) — an in-silico prediction, not a clinical call.

EXOSC9 p.Val129Phe

c.385G>T · rs771753934 · VCV2275073

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00512%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9777	likely pathogenic · top 6% in EXOSC9
REVEL	0.68	pathogenic-leaning
SaProt	LLR -16.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.22	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.46	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 0.99, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	34.0	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 0.00512% Admixed American · 3/58,596 alleles

Filtering AF 0.00136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000677%

Overall 0.000256% 4/1,565,208 alleles · very rare exomes 1/1,413,060 · genomes 3/152,148 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00512%	19,532
Remaining individualsnot grpmax-eligible	0.00165%	60,604

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.Val129Phe
Coding: c.385G>T
MANE Select: NM_005033
dbSNP: rs771753934
Type: single nucleotide variant
Location: chr4:121804622 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.44 · 8 PDB
Residue 129: 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.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-val129phe (accessed [today's date]).

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