Is SNCA p.Pro117Ser (c.349C>T) pathogenic?

SNCA p.Pro117Ser (c.349C>T) is classified Likely benign in SNCA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-17). AlphaMissense: likely benign (0.0861); Ultra-rare (popmax 0.0513%, eas); Associated with autosomal dominant Parkinson disease 1.

What condition is associated with SNCA p.Pro117Ser (c.349C>T)?

SNCA p.Pro117Ser (c.349C>T) is associated with autosomal dominant Parkinson disease 1, Lewy body dementia (ClinVar).

How common is SNCA p.Pro117Ser (c.349C>T) in the general population?

SNCA p.Pro117Ser (c.349C>T) is ultra-rare (popmax 0.0513%, 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.Pro117Ser (c.349C>T)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

SNCA p.Pro117Ser

c.349C>T · rs145138372 · VCV2038359

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0513%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal dominant Parkinson disease 1

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.392	indeterminate
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 109 kb · p 0.025 · regional, not allelic
Overall
CADD	22.3	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 0.0513% East Asian · 23/44,842 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.00155% 25/1,611,006 alleles · ultra-rare exomes 19/1,458,838 · genomes 6/152,168 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0513%	1,950
Remaining individualsnot grpmax-eligible	0.0016%	62,410
European (non-Finnish)	8.49e-05%	1,177,541

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.Pro117Ser
Coding: c.349C>T
MANE Select: NM_000345
dbSNP: rs145138372
Type: single nucleotide variant
Location: chr4:89729235 (GRCh38)
Gene constraint: LOEUF 0.691 · pLI 0.80 (gnomAD)
Structure: AlphaFold pLDDT 74.29 · 185 PDB
Residue 117: an α-helix; the 'disordered' region; the 'interaction with serf1a' region

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

Disease context

autosomal dominant Parkinson disease 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lewy body dementia

For Hereditary late-onset Parkinson disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

SNCA p.Pro117Thr Uncertain significance ★★ ⚠ same residue
SNCA p.Ala53Glu Pathogenic ★★ ⚠ same condition
SNCA p.Ala53Thr Pathogenic ★★ ⚠ same condition
SNCA p.His50Gln 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-pro117ser (accessed [today's date]).

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