SNCAIP

Chr 5

synuclein alpha interacting protein

Also known as: SYPH1, Sph1

NCBI Gene: 9627 ENSG00000064692 UniProt: Q9Y6H5 OMIM: 603779

The protein encoded by this gene interacts with alpha-synuclein in neuronal tissue and modulates protein degradation pathways through its effects on ubiquitin ligase activity. Mutations cause Parkinson's disease with autosomal recessive inheritance. This gene is highly constrained against loss-of-function variants, indicating that complete protein loss is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein containing several protein-protein interaction domains, including ankyrin-like repeats, a coiled-coil domain, and an ATP/GTP-binding motif. The encoded protein interacts with alpha-synuclein in neuronal tissue and may play a role in the formation of cytoplasmic inclusions and neurodegeneration. A mutation in this gene has been associated with Parkinson's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.55

Clinical Summary— SNCAIP

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

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ClinVar Variants

142 VUS of 205 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.000

Z-score 3.70

OE 0.35 (0.23–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.77Z-score

OE missense 0.90 (0.83–0.98)

438 obs / 485.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.23–0.55)

0≤0.351.4

Missense OE?0.90 (0.83–0.98)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 13 / 37.4Missense obs/exp: 438 / 485.5Syn Z: 0.25

This gene — mechanism propensity

0.6259th %ile

GOF

0.6444th %ile

LOF

0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

205 submitted variants in ClinVar

ClinVar

Classification Summary

VUS142

Likely Benign33

Benign12

Conflicting2

142

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	115	16	10	142
Likely Benign	0	13	4	16	33
Benign	0	3	2	7	12
Conflicting	—				2
Total	1	131	22	33	189

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

21 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap SNCAIP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →