Is EXOSC3 p.Val80Phe (c.238G>T) pathogenic?

EXOSC3 p.Val80Phe (c.238G>T) is classified Pathogenic/Likely pathogenic in EXOSC3 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.9659); Ultra-rare (popmax 0.0605%, amr); Associated with EXOSC3-related disorder.

What condition is associated with EXOSC3 p.Val80Phe (c.238G>T)?

EXOSC3 p.Val80Phe (c.238G>T) is associated with EXOSC3-related disorder, pontocerebellar hypoplasia type 1B, pontocerebellar hypoplasia (ClinVar).

How common is EXOSC3 p.Val80Phe (c.238G>T) in the general population?

EXOSC3 p.Val80Phe (c.238G>T) is ultra-rare (popmax 0.0605%, amr) (gnomAD).

What do computational predictors say about EXOSC3 p.Val80Phe (c.238G>T)?

AlphaMissense predicts likely pathogenic (score 0.9659) — an in-silico prediction, not a clinical call.

EXOSC3 p.Val80Phe

c.238G>T · rs374550999 · VCV129024

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0605%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EXOSC3-related disorder

Computational evidence

Protein change
AlphaMissense	0.9659	likely pathogenic ✓ concordant with ClinVar
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -14.21	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 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 4,362 bp · p 0.097 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0605% Admixed American · 36/59,540 alleles

Filtering AF 0.0448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0395%

Overall 0.016% 258/1,608,334 alleles · ultra-rare exomes 121/1,455,964 · genomes 137/152,370 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	10.7%	9
Admixed Americangrpmax	0.0605%	1,654
South Asian	0.042%	2,384
Middle Eastern	0.0165%	6,050
European (non-Finnish)	0.00704%	14,198
Remaining individualsnot grpmax-eligible	0.00321%	31,118

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val80Phe
Coding: c.238G>T
MANE Select: NM_016042
dbSNP: rs374550999
Type: single nucleotide variant
Location: chr9:37784807 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.26 · 8 PDB
Residue 80: a β-strand; a UniProt-annotated variant site (in)

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

Disease context

EXOSC3-related disorder

Also linked: pontocerebellar hypoplasia type 1B pontocerebellar hypoplasia

Similar variants

EXOSC3 p.Val80= Likely benign ★ same residue
EXOSC3 p.Val80Leu Likely pathogenic ★ same residue
EXOSC3 p.Arg186Ter Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Asp132Ala Pathogenic ★★ same condition
EXOSC3 p.Gly191Asp Likely pathogenic ★★ same condition
EXOSC3 p.Gly31Ala Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
EXOSC3 p.Met1Val Pathogenic/Likely 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-val80phe (accessed [today's date]).

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