Is EXOSC3 p.Val99fs (c.294_303del) pathogenic?

EXOSC3 p.Val99fs (c.294303del) is classified Pathogenic in EXOSC3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-04). Very rare (popmax 8.5e-05%, nfe); Associated with pontocerebellar hypoplasia type 1B.

What condition is associated with EXOSC3 p.Val99fs (c.294_303del)?

EXOSC3 p.Val99fs (c.294_303del) is associated with pontocerebellar hypoplasia type 1B (ClinVar).

How common is EXOSC3 p.Val99fs (c.294_303del) in the general population?

EXOSC3 p.Val99fs (c.294_303del) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

EXOSC3 p.Val99fs

c.294_303del · rs672601331 · VCV31690

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Conditions

pontocerebellar hypoplasia type 1B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,177,014 alleles

Overall 6.25e-05% 1/1,599,712 alleles · very rare exomes 1/1,447,360 · genomes 0/152,352 · 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: EXOSC3
Protein: p.Val99fs
Coding: c.294_303del
MANE Select: NM_016042
dbSNP: rs672601331
Type: Deletion
Location: chr9:37784742 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.26 · 8 PDB

Full EXOSC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pontocerebellar hypoplasia type 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EXOSC3 c.624_626+1del Likely pathogenic ★★ same condition
EXOSC3 p.Asn56fs Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Glu38fs Pathogenic ★★ same condition
EXOSC3 p.Pro52fs Pathogenic ★★ same condition
EXOSC3 p.Tyr143fs Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Ser270del Uncertain significance ★★ same condition
EXOSC3 p.Arg154fs Likely pathogenic ★ same condition
EXOSC3 p.Arg58fs Pathogenic ★ 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/exosc3-p-val99fs (accessed [today's date]).

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