Is SNCA p.Thr81= (c.243A>G) pathogenic?

SNCA p.Thr81= (c.243A>G) is classified Benign/Likely benign in SNCA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-04). Rare (popmax 0.467%, sas); Associated with Lewy body dementia.

What condition is associated with SNCA p.Thr81= (c.243A>G)?

SNCA p.Thr81= (c.243A>G) is associated with Lewy body dementia, autosomal dominant Parkinson disease 1, autosomal dominant Parkinson disease 4 (ClinVar).

How common is SNCA p.Thr81= (c.243A>G) in the general population?

SNCA p.Thr81= (c.243A>G) is rare (popmax 0.467%, sas) (gnomAD).

SNCA p.Thr81=

c.243A>G · rs568436589 · VCV350106

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.467%, sas)

Conditions

Lewy body dementia

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 -8.9	GERP -3.6
Overall
CADD	1.212	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.467% South Asian · 425/91,078 alleles

Filtering AF 0.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.416%

Overall 0.0277% 447/1,614,216 alleles · rare exomes 418/1,461,890 · genomes 29/152,326 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.467%	214
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0288%	3,473
European (non-Finnish)	0.000169%	590,019

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.Thr81=
Coding: c.243A>G
MANE Select: NM_000345
dbSNP: rs568436589
Type: single nucleotide variant
Location: chr4:89822309 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.80 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 185 PDB
Residue 81: a β-strand

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

Disease context

Lewy body dementia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant Parkinson disease 1 autosomal dominant Parkinson disease 4

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-thr81 (accessed [today's date]).

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