Is VPS13C p.Ala643= (c.1929A>C) pathogenic?

VPS13C p.Ala643= (c.1929A>C) is classified Benign/Likely benign in VPS13C (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.09%, nfe); Associated with autosomal recessive early-onset Parkinson disease 23.

What condition is associated with VPS13C p.Ala643= (c.1929A>C)?

VPS13C p.Ala643= (c.1929A>C) is associated with autosomal recessive early-onset Parkinson disease 23 (ClinVar).

How common is VPS13C p.Ala643= (c.1929A>C) in the general population?

VPS13C p.Ala643= (c.1929A>C) is low-frequency (popmax 1.09%, nfe) (gnomAD).

How is Young-onset Parkinson disease inherited?

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

VPS13C p.Ala643=

c.1929A>C · rs115871350 · VCV781720

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.09%, nfe)

Conditions

autosomal recessive early-onset Parkinson disease 23

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -2.9, phastCons 0.72
Overall
CADD	7.264	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.09% European (non-Finnish) · 12,820/1,177,558 alleles

Filtering AF 1.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.07%

Overall 0.937% 15,047/1,605,036 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.78%	56
European (non-Finnish)grpmax	1.09%	92
Ashkenazi Jewishnot grpmax-eligible	0.871%	115
Remaining individualsnot grpmax-eligible	0.743%	135
Admixed American	0.442%	226
African / African-American	0.174%	575
Middle Eastern	0.0996%	1,004
South Asian	0.00788%	12,689

Finnish 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: VPS13C
Protein: p.Ala643=
Coding: c.1929A>C
MANE Select: NM_020821
dbSNP: rs115871350
Type: single nucleotide variant
Location: chr15:61982559 (GRCh38)
Gene constraint: LOEUF 0.857 · pLI <0.01 (gnomAD)

Full VPS13C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive early-onset Parkinson disease 23 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Young-onset Parkinson disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

VPS13C p.Ala643Thr Uncertain significance ★ ⚠ same residue
VPS13C c.5868+1G>A Likely pathogenic ★★ same condition
VPS13C p.Arg2936Ter Pathogenic/Likely pathogenic ★★ same condition
VPS13C p.Arg3652Ter Pathogenic/Likely pathogenic ★★ same condition
VPS13C p.Arg371Ter Pathogenic/Likely pathogenic ★★ same condition
VPS13C p.Gln3257Ter Pathogenic ★★ same condition
VPS13C p.Glu3354Ter Pathogenic ★★ same condition
VPS13C p.Gly1389Arg 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/vps13c-p-ala643 (accessed [today's date]).

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