SYNJ1

Chr 21

synaptojanin 1

Also known as: DEE53, EIEE53, INPP5G, PARK20

NCBI Gene: 8867 ENSG00000159082 UniProt: O43426

The protein is a phosphoinositide phosphatase that regulates membrane phosphatidylinositol-4,5-bisphosphate levels, affecting synaptic transmission and membrane trafficking. Autosomal recessive mutations cause developmental and epileptic encephalopathy 53 and early-onset Parkinson disease 20. The pathogenic mechanism involves disruption of synaptic function and cellular membrane trafficking processes.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a phosphoinositide phosphatase that regulates levels of membrane phosphatidylinositol-4,5-bisphosphate. As such, expression of this enzyme may affect synaptic transmission and membrane trafficking. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtParkinson disease 20, early-onset

UniProtDevelopmental and epileptic encephalopathy 53

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · genetic developmental and epileptic encephalopathy · AR · ClinGen 2022

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.33

LOEUF· LoF intol.

—

Mechanism

📖

GeneReview available — SYNJ1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.427

Z-score 6.61

OE 0.22 (0.16–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.25Z-score

OE missense 0.78 (0.73–0.83)

667 obs / 851.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.22 (0.16–0.33)

0≤0.351.4

Missense OE?0.78 (0.73–0.83)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 19 / 84.5Missense obs/exp: 667 / 851.7Syn Z: 0.41

Background carrier burden — how many people carry a rare variant somewhere in SYNJ1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 36

1,815 rare PASS variants

Rare truncating (LoF)

1 in 1,100

194 rare PASS variants

Rare synonymous (reference)

1 in 75

746 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SYNJ1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 56	1 in 1,800
South Asian	~43k	1 in 34	1 in 340
Remaining (unassigned)	~30k	1 in 26	1 in 490
European (Finnish)	~27k	1 in 94	1 in 3,600
Admixed American	~22k	1 in 36	1 in 1,400
African / African American	~21k	1 in 39	1 in 380
East Asian	~20k	1 in 45	1 in 950
Ashkenazi Jewish	~13k	1 in 100	≈ 1 in 4,100
Middle Eastern	~2,884	1 in 35	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 27 of 31 coding exons well covered in gnomAD exomes; exons 3, 6, 8, 25 marginal. Genomes: all 31.? see exons ↓