Is SNCA p.Ala53Val (c.158C>T) pathogenic?

SNCA p.Ala53Val (c.158C>T) is classified Conflicting classifications of pathogenicity in SNCA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-06-05). AlphaMissense: likely benign (0.1564); Ultra-rare (popmax 0.0134%, eas); Associated with autosomal dominant Parkinson disease 4.

What condition is associated with SNCA p.Ala53Val (c.158C>T)?

SNCA p.Ala53Val (c.158C>T) is associated with autosomal dominant Parkinson disease 4, Lewy body dementia, autosomal dominant Parkinson disease 1 (ClinVar).

How common is SNCA p.Ala53Val (c.158C>T) in the general population?

SNCA p.Ala53Val (c.158C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

How is Hereditary late-onset Parkinson disease inherited?

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

What do computational predictors say about SNCA p.Ala53Val (c.158C>T)?

AlphaMissense predicts likely benign (score 0.1564) — an in-silico prediction, not a clinical call.

SNCA p.Ala53Val

c.158C>T · rs542171324 · VCV1393530

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1564 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal dominant Parkinson disease 4

Computational evidence

Protein change
AlphaMissense	0.1564	likely benign
REVEL	0.536	indeterminate
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 109 kb · p 0.025 · regional, not allelic
Overall
CADD	26.5	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 0.0134% East Asian · 6/44,800 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.000372% 6/1,612,298 alleles · ultra-rare exomes 5/1,460,262 · genomes 1/152,036 · 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.Ala53Val
Coding: c.158C>T
MANE Select: NM_000345
dbSNP: rs542171324
Type: single nucleotide variant
Location: chr4:89828148 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.80 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 185 PDB
Residue 53: a UniProt-annotated variant site (in park1; no effect on osmotic stress-induced phosphorylation; increases oligomerization); a β-strand; 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 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lewy body dementia autosomal dominant Parkinson disease 1

For Hereditary late-onset Parkinson disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

SNCA p.Ala53Glu Pathogenic ★★ ⚠ same residue
SNCA p.Ala53Thr Pathogenic ★★ ⚠ same residue
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-ala53val (accessed [today's date]).

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