# NM_203446.3(SYNJ1):c.1533A>G (p.Ser511=)

https://sugi.bio/variant/synj1-p-ser511

## Summary

**SYNJ1 p.Ser511= (c.1533A>G)** is classified **Uncertain significance** in SYNJ1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 53.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2516675789 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the SYNJ1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy, 53.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016224/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SYNJ1](https://sugi.bio/atlas/gene/SYNJ1/) |
| Protein change (HGVS p.) | p.Ser511= |
| Coding change (HGVS c.) | c.1533A>G |
| MANE Select transcript | [NM_203446](https://www.ncbi.nlm.nih.gov/nuccore/NM_203446) |
| dbSNP | [rs2516675789](https://www.ncbi.nlm.nih.gov/snp/rs2516675789/) |
| Variant type | single nucleotide variant |
| Location | chr21:32676333-32676333 (GRCh38) |
| ClinVar | [VCV2021269](https://www.ncbi.nlm.nih.gov/clinvar/variation/2021269/) |

**All HGVS expressions:** `NC_000021.8:g.34048643T>C`, `NC_000021.9:g.32676333T>C`, `NG_030017.2:g.56707A>G`, `NM_001160302.2:c.1533A>G`, `NM_001160306.2:c.1519+2312A>G`, `NM_003895.4:c.1650A>G`, `NM_203446.3:c.1533A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.40) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.934, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.32**, donor loss **0.40**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.32**, donor loss **0.40**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.45** (loss), gain 0.00 / loss 0.45. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**SYNJ1** population constraint: LOEUF 0.539, pLI 0.0018295, missense-Z 2.9259. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **genetic developmental and epileptic encephalopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.09, 34% of residues very-high.

**5 experimental structure(s)** (PDB): [1W80](https://www.rcsb.org/structure/1W80), [2DNR](https://www.rcsb.org/structure/2DNR), [2VJ0](https://www.rcsb.org/structure/2VJ0), [7A0V](https://www.rcsb.org/structure/7A0V), [7A17](https://www.rcsb.org/structure/7A17).

## What this gene does {#gene-function}

*Describes the biological roles of SYNJ1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** SYNJ1's established molecular role includes phosphatidylinositol-3-phosphate phosphatase activity.


### Pathways affected {#pathways}

SYNJ1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Synthesis of IP2, IP, and Ins in the cytosol](https://reactome.org/content/detail/R-HSA-1855183) | curated |
| [Synthesis of IP3 and IP4 in the cytosol](https://reactome.org/content/detail/R-HSA-1855204) | curated |
| [Synthesis of PIPs at the plasma membrane](https://reactome.org/content/detail/R-HSA-1660499) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** phosphatidylinositol-3-phosphate phosphatase activity, phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity, phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity, phosphatidylinositol-4-phosphate phosphatase activity, phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity, inositol-1,4,5-trisphosphate 5-phosphatase activity.

**Biological process:** learning, phosphatidylinositol catabolic process, synaptic vesicle recycling, phosphatidylinositol dephosphorylation, synaptic vesicle endocytosis, 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-15 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 53](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-53/), [early-onset Parkinson disease 20](https://sugi.bio/atlas/disease/early-onset-parkinson-disease-20/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 53, Early-onset Parkinson disease 20, Epileptic encephalopathy, early infantile, 53, PARKINSON DISEASE 20, AUTOSOMAL RECESSIVE EARLY-ONSET.

## Similar variants {#similar}

Related SYNJ1 variant pages (same residue, condition, or type): [SYNJ1 c.1201-2A>G](/variant/synj1-c-1201-minus-2a-g), [SYNJ1 c.2461+2T>C](/variant/synj1-c-2461-plus-2t-c), [SYNJ1 c.3478+1G>A](/variant/synj1-c-3478-plus-1g-a), [SYNJ1 p.Arg219Gln](/variant/synj1-p-arg219gln), [SYNJ1 p.Arg534Ter](/variant/synj1-p-arg534ter), [SYNJ1 p.Arg709Ter](/variant/synj1-p-arg709ter), [SYNJ1 p.Gln748Ter](/variant/synj1-p-gln748ter), [SYNJ1 c.-42A>G](/variant/synj1-c-minus-42a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2021269). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*