Is SYNJ1 p.Val940Phe (c.2818G>T) pathogenic?

SYNJ1 p.Val940Phe (c.2818G>T) is classified Uncertain significance in SYNJ1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-26). Very rare (popmax 0.00167%, amr); Associated with early-onset Parkinson disease 20.

What condition is associated with SYNJ1 p.Val940Phe (c.2818G>T)?

SYNJ1 p.Val940Phe (c.2818G>T) is associated with early-onset Parkinson disease 20, developmental and epileptic encephalopathy, 53 (ClinVar).

How common is SYNJ1 p.Val940Phe (c.2818G>T) in the general population?

SYNJ1 p.Val940Phe (c.2818G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Young-onset Parkinson disease inherited?

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

SYNJ1 p.Val940Phe

c.2818G>T · rs890538025 · VCV1348995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

early-onset Parkinson disease 20

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.898	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 80 kb · p 9.8e-17 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,004 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000496% 8/1,612,722 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,219
Admixed Americangrpmax	0.00167%	60,004
African / African-American	0.00134%	74,850
European (non-Finnish)	0.000339%	294,734

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val940Phe
Coding: c.2818G>T
MANE Select: NM_203446
dbSNP: rs890538025
Type: single nucleotide variant
Location: chr21:32653344 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.09 · 5 PDB
Residue 940: a β-strand; the rrm domain

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.1201-2A>G Likely pathogenic ★★ same condition
SYNJ1 c.2461+2T>C Likely pathogenic ★★ same condition
SYNJ1 c.3478+1G>A Likely pathogenic ★★ same condition
SYNJ1 p.Arg219Gln Pathogenic ★★ same condition
SYNJ1 p.Arg534Ter Pathogenic/Likely pathogenic ★★ same condition
SYNJ1 p.Arg709Ter Pathogenic/Likely pathogenic ★★ same condition
SYNJ1 p.Gln748Ter Pathogenic/Likely pathogenic ★★ same condition
SYNJ1 c.-42A>G Uncertain significance ★★ 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-val940phe (accessed [today's date]).

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