Is SNCA p.Thr72= (c.216G>A) pathogenic?

SNCA p.Thr72= (c.216G>A) is classified Conflicting classifications of pathogenicity in SNCA (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-08). Rare (popmax 0.148%, mid); Associated with Parkinson Disease, Dominant.

What condition is associated with SNCA p.Thr72= (c.216G>A)?

SNCA p.Thr72= (c.216G>A) is associated with Parkinson Disease, Dominant, Lewy body dementia, autosomal dominant Parkinson disease 1 (ClinVar).

How common is SNCA p.Thr72= (c.216G>A) in the general population?

SNCA p.Thr72= (c.216G>A) is rare (popmax 0.148%, mid) (gnomAD).

SNCA p.Thr72=

c.216G>A · rs144758871 · VCV705925

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Conditions

Parkinson Disease, Dominant

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 -2.9	GERP -5.4
Overall
CADD	4.405	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.148% Middle Eastern · 9/6,084 alleles

Filtering AF 0.0772% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0576%

Overall 0.0159% 256/1,614,072 alleles · rare exomes 224/1,461,886 · genomes 32/152,186 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.28%	357
Middle Easterngrpmax	0.148%	676
Remaining individualsnot grpmax-eligible	0.0352%	2,840
South Asian	0.0231%	4,337
Admixed American	0.01%	10,001
European (non-Finnish)	0.00949%	10,536
African / African-American	0.004%	24,976

Ashkenazi Jewish 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: SNCA
Protein: p.Thr72=
Coding: c.216G>A
MANE Select: NM_000345
dbSNP: rs144758871
Type: single nucleotide variant
Location: chr4:89822336 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.80 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 185 PDB
Residue 72: a β-strand

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

Disease context

Parkinson Disease, Dominant

Also linked: Lewy body dementia autosomal dominant Parkinson disease 1

Similar variants

SNCA p.Thr72Lys Uncertain significance ★ ⚠ same residue
SNCA p.Ala53Glu Pathogenic ★★ ⚠ same condition
SNCA p.Ala53Thr Pathogenic ★★ ⚠ same condition
SNCA c.-219G>C Uncertain significance ★★ same condition
SNCA c.*2037T>C Uncertain significance ★★ same condition
SNCA p.His50Gln Uncertain significance ★★ ⚠ same condition
SNCA p.Pro117Thr Uncertain significance ★★ ⚠ same condition
SNCA p.Pro128Thr 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/snca-p-thr72 (accessed [today's date]).

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