Is SNCA p.Thr33= (c.99A>G) pathogenic?

SNCA p.Thr33= (c.99A>G) is classified Likely benign in SNCA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-03). Very rare (popmax 0.000932%, nfe); Associated with autosomal dominant Parkinson disease 1.

What condition is associated with SNCA p.Thr33= (c.99A>G)?

SNCA p.Thr33= (c.99A>G) is associated with autosomal dominant Parkinson disease 1, Lewy body dementia (ClinVar).

How common is SNCA p.Thr33= (c.99A>G) in the general population?

SNCA p.Thr33= (c.99A>G) is very rare (popmax 0.000932%, nfe) (gnomAD).

How is Hereditary late-onset Parkinson disease inherited?

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

SNCA p.Thr33=

c.99A>G · rs766497794 · VCV2925064

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Conditions

autosomal dominant Parkinson disease 1

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 0.27	GERP -5.6, phastCons 1
Overall
CADD	9.872	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,180,048 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000681% 11/1,614,100 alleles · very rare exomes 9/1,461,874 · genomes 2/152,226 · joint denominator

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: SNCA
Protein: p.Thr33=
Coding: c.99A>G
MANE Select: NM_000345
dbSNP: rs766497794
Type: single nucleotide variant
Location: chr4:89835569 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.80 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 185 PDB
Residue 33: the '4 x 11 aa tandem repeats of [egs]-k-t-k-[eq]-[gq]-v-x(4)' region

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

Disease context

autosomal dominant Parkinson disease 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lewy body dementia

For Hereditary late-onset Parkinson disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

SNCA p.Ala53Glu Pathogenic ★★ ⚠ same condition
SNCA p.Ala53Thr Pathogenic ★★ ⚠ same condition
SNCA p.His50Gln Uncertain significance ★★ ⚠ same condition
SNCA p.Pro117Thr Uncertain significance ★★ ⚠ same condition
SNCA p.Pro128Thr Uncertain significance ★★ ⚠ same condition
SNCA c.121+11C>T Benign/Likely benign ★★ same condition
SNCA c.391-16A>G Likely benign ★★ same condition
SNCA c.*139T>G Benign/Likely benign ★★ 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/snca-p-thr33 (accessed [today's date]).

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