Is SNCA p.Lys96Arg (c.287A>G) pathogenic?

SNCA p.Lys96Arg (c.287A>G) is classified Benign/Likely benign in SNCA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.0854); Rare (popmax 0.313%, sas); Associated with Parkinson Disease, Dominant.

What condition is associated with SNCA p.Lys96Arg (c.287A>G)?

SNCA p.Lys96Arg (c.287A>G) is associated with Parkinson Disease, Dominant, Lewy body dementia, autosomal dominant Parkinson disease 1 (ClinVar).

How common is SNCA p.Lys96Arg (c.287A>G) in the general population?

SNCA p.Lys96Arg (c.287A>G) is rare (popmax 0.313%, sas) (gnomAD).

What do computational predictors say about SNCA p.Lys96Arg (c.287A>G)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

SNCA p.Lys96Arg

c.287A>G · rs548523899 · VCV704527

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.313%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Parkinson Disease, Dominant

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -9.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.42	GERP -1.3, phastCons 0.023
Regional constraint	o/e 0.83	unconstrained · MANE · 109 kb · p 0.025 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.313% South Asian · 285/91,080 alleles

Filtering AF 0.283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.271%

Overall 0.0242% 390/1,614,170 alleles · rare exomes 374/1,461,890 · genomes 16/152,280 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.313%	320
Remaining individualsnot grpmax-eligible	0.0304%	3,290
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00686%	14,568
Finnishnot grpmax-eligible	0.00468%	21,347
Admixed American	0.00167%	60,020

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.Lys96Arg
Coding: c.287A>G
MANE Select: NM_000345
dbSNP: rs548523899
Type: single nucleotide variant
Location: chr4:89822265 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.80 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 185 PDB
Residue 96: 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.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
SNCA c.121+11C>T 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-lys96arg (accessed [today's date]).

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