Is VPS41 p.Ser285Pro (c.853T>C) pathogenic?

VPS41 p.Ser285Pro (c.853T>C) is classified Likely pathogenic in VPS41 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9001); Very rare (popmax 0.00102%, nfe); Associated with spinocerebellar ataxia, autosomal recessive 29.

What condition is associated with VPS41 p.Ser285Pro (c.853T>C)?

VPS41 p.Ser285Pro (c.853T>C) is associated with spinocerebellar ataxia, autosomal recessive 29, hyperimmunoglobulinemia D with periodic fever (ClinVar).

How common is VPS41 p.Ser285Pro (c.853T>C) in the general population?

VPS41 p.Ser285Pro (c.853T>C) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about VPS41 p.Ser285Pro (c.853T>C)?

AlphaMissense predicts likely pathogenic (score 0.9001) — an in-silico prediction, not a clinical call.

VPS41 p.Ser285Pro

c.853T>C · rs544223875 · VCV1175718

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9001 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spinocerebellar ataxia, autosomal recessive 29

Computational evidence

Protein change
AlphaMissense	0.9001	likely pathogenic ✓ concordant with ClinVar
REVEL	0.266	benign-leaning
SaProt	LLR -14.21	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 183 kb · p 5.8e-06 · regional, not allelic
Overall
CADD	24.1	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 0.00102% European (non-Finnish) · 12/1,177,520 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000745% 12/1,611,172 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: VPS41
Protein: p.Ser285Pro
Coding: c.853T>C
MANE Select: NM_014396
dbSNP: rs544223875
Type: single nucleotide variant
Location: chr7:38776708 (GRCh38)
Gene constraint: LOEUF 0.904 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 285: a UniProt-annotated variant site (in scar29; decreased protein abundance; cannot form a functional hops complex; causes a kinetic defect in the endosome-lysosome fusion process); the 'interaction with arl8b' region

Full VPS41 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia, autosomal recessive 29 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperimmunoglobulinemia D with periodic fever

Similar variants

VPS41 p.Ala804Gly Uncertain significance ★★ ⚠ same condition
VPS41 p.Val539Ile Uncertain significance ★★ ⚠ same condition
VPS41 c.385-2A>G Likely pathogenic ★ same condition
VPS41 p.Arg416His Likely pathogenic ★ ⚠ same condition
VPS41 p.Arg662Ter Likely pathogenic ★ same condition
VPS41 p.Arg667Ter Likely pathogenic ★ same condition
VPS41 p.Tyr612Ter Likely pathogenic ★ same condition
VPS41 p.Gln541Arg 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/vps41-p-ser285pro (accessed [today's date]).

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