Is SNCA p.Leu100= (c.298T>C) pathogenic?

SNCA p.Leu100= (c.298T>C) is classified Likely benign in SNCA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-23). Ultra-rare (popmax 0.067%, sas); Associated with Lewy body dementia.

What condition is associated with SNCA p.Leu100= (c.298T>C)?

SNCA p.Leu100= (c.298T>C) is associated with Lewy body dementia, autosomal dominant Parkinson disease 1 (ClinVar).

How common is SNCA p.Leu100= (c.298T>C) in the general population?

SNCA p.Leu100= (c.298T>C) is ultra-rare (popmax 0.067%, sas) (gnomAD).

SNCA p.Leu100=

c.298T>C · rs138969470 · VCV350105

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.067%, sas)

Conditions

Lewy body dementia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6	GERP -3.3
Overall
CADD	0.681	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.067% South Asian · 61/91,084 alleles

Filtering AF 0.0535% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.0216% 349/1,614,132 alleles · ultra-rare exomes 326/1,461,886 · genomes 23/152,246 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.067%	1,493
East Asian	0.029%	3,452
African / African-American	0.0213%	4,690
Remaining individualsnot grpmax-eligible	0.0208%	4,808
European (non-Finnish)	0.0208%	4,816
Admixed American	0.00167%	60,022

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.Leu100=
Coding: c.298T>C
MANE Select: NM_000345
dbSNP: rs138969470
Type: single nucleotide variant
Location: chr4:89822254 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.80 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 185 PDB
Residue 100: the 'disordered' region

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

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-leu100 (accessed [today's date]).

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