Is STUB1 p.Pro228Ser (c.682C>T) pathogenic?

STUB1 p.Pro228Ser (c.682C>T) is classified Pathogenic in STUB1 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-01-04). AlphaMissense: likely pathogenic (0.9954); Very rare (popmax 0.000766%, nfe); Associated with spinocerebellar ataxia 48.

What condition is associated with STUB1 p.Pro228Ser (c.682C>T)?

STUB1 p.Pro228Ser (c.682C>T) is associated with spinocerebellar ataxia 48 (ClinVar).

How common is STUB1 p.Pro228Ser (c.682C>T) in the general population?

STUB1 p.Pro228Ser (c.682C>T) is very rare (popmax 0.000766%, nfe) (gnomAD).

How is Spinocerebellar ataxia type 48 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about STUB1 p.Pro228Ser (c.682C>T)?

AlphaMissense predicts likely pathogenic (score 0.9954) — an in-silico prediction, not a clinical call.

STUB1 p.Pro228Ser

c.682C>T · rs2039691550 · VCV997700

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000766%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

spinocerebellar ataxia 48

Computational evidence

Protein change
AlphaMissense	0.9954	likely pathogenic ✓ concordant with ClinVar
REVEL	0.349	indeterminate
SaProt	LLR -13.77	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,960 bp · p 0.064 · regional, not allelic
Overall
CADD	27.4	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 0.000766% European (non-Finnish) · 9/1,175,210 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000618% 9/1,455,512 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: STUB1
Protein: p.Pro228Ser
Coding: c.682C>T
MANE Select: NM_005861
dbSNP: rs2039691550
Type: single nucleotide variant
Location: chr16:682177 (GRCh38)
Gene constraint: LOEUF 1.294 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84 · 27 PDB
Residue 228: the u-box domain; the 'required for ubiquitination of foxo1' region

Full STUB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia 48 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spinocerebellar ataxia type 48 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

STUB1 p.Asn65Ser Pathogenic/Likely pathogenic ★★ same condition
STUB1 p.Glu185Lys Uncertain significance ★★ ⚠ same condition
STUB1 p.Gly249Val Uncertain significance ★★ ⚠ same condition
STUB1 p.Ile290Thr Uncertain significance ★★ ⚠ same condition
STUB1 p.Lys95Glu Uncertain significance ★★ ⚠ same condition
STUB1 p.Tyr252Cys Uncertain significance ★★ ⚠ same condition
STUB1 p.Leu214= Benign/Likely benign ★★ same condition
STUB1 p.Ala52Gly 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/stub1-p-pro228ser (accessed [today's date]).

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