Is SNCA p.Pro117Thr (c.349C>A) pathogenic?

SNCA p.Pro117Thr (c.349C>A) is classified Uncertain significance in SNCA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.072); Very rare (popmax 0.00892%, nfe); Associated with Lewy body dementia.

What condition is associated with SNCA p.Pro117Thr (c.349C>A)?

SNCA p.Pro117Thr (c.349C>A) is associated with Lewy body dementia, autosomal dominant Parkinson disease 1, autosomal dominant Parkinson disease 4 (ClinVar).

How common is SNCA p.Pro117Thr (c.349C>A) in the general population?

SNCA p.Pro117Thr (c.349C>A) is very rare (popmax 0.00892%, nfe) (gnomAD).

What do computational predictors say about SNCA p.Pro117Thr (c.349C>A)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

SNCA p.Pro117Thr

c.349C>A · rs145138372 · VCV652694

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Lewy body dementia

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -8.30	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	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% European (non-Finnish) · 105/1,177,546 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00702%

Overall 0.00708% 114/1,610,884 alleles · very rare exomes 105/1,458,834 · genomes 9/152,050 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00892%	11,215
Admixed American	0.00667%	14,993
African / African-American	0.00534%	18,711
Remaining individualsnot grpmax-eligible	0.0016%	62,388

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.Pro117Thr
Coding: c.349C>A
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

Lewy body dementia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant Parkinson disease 1 autosomal dominant Parkinson disease 4

Similar variants

SNCA p.Pro117Ser Likely benign ★ 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-pro117thr (accessed [today's date]).

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