Is VPS13D p.Pro2886= (c.8658A>C) pathogenic?

VPS13D p.Pro2886= (c.8658A>C) is classified Benign in VPS13D (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 91.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive cerebellar ataxia-saccadic intrusion syndrome.

What condition is associated with VPS13D p.Pro2886= (c.8658A>C)?

VPS13D p.Pro2886= (c.8658A>C) is associated with autosomal recessive cerebellar ataxia-saccadic intrusion syndrome (ClinVar).

VPS13D p.Pro2886=

Q: How common is VPS13D p.Pro2886= (c.8658A>C) in the general population?

VPS13D p.Pro2886= (c.8658A>C) is common (popmax 91.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Autosomal recessive cerebellar ataxia-movement disorder syndrome inherited?

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

c.8658A>C · rs28551666 · VCV1274892

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 91.1%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal recessive cerebellar ataxia-saccadic intrusion syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.092	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -4.9
Overall
CADD	0.188	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 91.1% East Asian · 40,867/44,842 alleles

Filtering AF 90.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 90.1%

Overall 80% 1,290,061/1,613,470 alleles · common exomes 1,170,654/1,461,610 · genomes 119,407/151,860 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	91.7%	1
East Asiangrpmax	91.1%	1
Middle Eastern	83.9%	1
Remaining individualsnot grpmax-eligible	80.7%	1
European (non-Finnish)	80.4%	1
South Asian	80.1%	1
Ashkenazi Jewishnot grpmax-eligible	77%	1
Finnishnot grpmax-eligible	76%	1
African / African-American	75.5%	1
Admixed American	72.9%	1

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: VPS13D
Protein: p.Pro2886=
Coding: c.8658A>C
MANE Select: NM_015378
dbSNP: rs28551666
Type: single nucleotide variant
Location: chr1:12341811 (GRCh38)
Gene constraint: LOEUF 0.426 · pLI 1.00 (gnomAD)
Residue 2886: a UniProt-annotated variant site (in scar4); a UniProt-annotated variant site (in scar4; altered mitochondrial morphology in patient cells); a UniProt-annotated variant site (in scar4; decreased protein abundance; altered mitochondrial morphology in patient cells)

Full VPS13D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive cerebellar ataxia-saccadic intrusion syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive cerebellar ataxia-movement disorder syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Childhood, Elderly, Infancy

Similar variants

VPS13D p.Pro2886Leu Uncertain significance ★ same residue
VPS13D c.941+3A>G Pathogenic/Likely pathogenic ★★ same condition
VPS13D p.Ala4139Val Likely pathogenic ★★ ⚠ same condition
VPS13D p.Arg316Ter Pathogenic/Likely pathogenic ★★ same condition
VPS13D p.Arg3253Ter Pathogenic/Likely pathogenic ★★ same condition
VPS13D p.Gly1190Asp Pathogenic/Likely pathogenic ★★ same condition
VPS13D p.Ala3688Thr Uncertain significance ★★ ⚠ same condition
VPS13D p.Arg1036Gln 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/vps13d-p-pro2886 (accessed [today's date]).

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