Is SYNJ1 p.Val640fs (c.1918_1921del) pathogenic?

SYNJ1 p.Val640fs (c.19181921del) is classified Pathogenic/Likely pathogenic in SYNJ1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-08). Very rare (popmax 6.84e-05%); Associated with early-onset Parkinson disease 20.

What condition is associated with SYNJ1 p.Val640fs (c.1918_1921del)?

SYNJ1 p.Val640fs (c.1918_1921del) is associated with early-onset Parkinson disease 20, developmental and epileptic encephalopathy, 53 (ClinVar).

How common is SYNJ1 p.Val640fs (c.1918_1921del) in the general population?

SYNJ1 p.Val640fs (c.1918_1921del) is very rare (popmax 6.84e-05%) (gnomAD).

How is Young-onset Parkinson disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SYNJ1 p.Val640fs

c.1918_1921del · rs1488690709 · VCV915309

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

early-onset Parkinson disease 20

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 33
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,796 alleles · very rare

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: SYNJ1
Protein: p.Val640fs
Coding: c.1918_1921del
MANE Select: NM_203446
dbSNP: rs1488690709
Type: Microsatellite
Location: chr21:32666464 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.09 · 5 PDB
Residue 640: the 5-ppase domain; a β-strand

Full SYNJ1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

early-onset Parkinson disease 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 53

For Young-onset Parkinson disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SYNJ1 c.*719CT[1] Uncertain significance ★★ same condition
SYNJ1 c.-46GAG[5] Uncertain significance ★ same condition
SYNJ1 p.His336_Gln337insHis Uncertain significance ★ same condition
SYNJ1 p.Leu827del Uncertain significance ★ same condition
SYNJ1 p.Pro1093_Leu1094insPro Uncertain significance ★ same condition
SYNJ1 p.Pro1129del Uncertain significance ★ same condition
SYNJ1 c.1510+16_1510+17del Benign ★ same condition
SYNJ1 c.1511-16_1511-14del 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/synj1-p-val640fs (accessed [today's date]).

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