Is SYNJ1 p.Phe128= (c.384T>C) pathogenic?

SYNJ1 p.Phe128= (c.384T>C) is classified Conflicting classifications of pathogenicity in SYNJ1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-07). Very rare (popmax 0.000424%, nfe); Associated with developmental and epileptic encephalopathy, 53.

How common is SYNJ1 p.Phe128= (c.384T>C) in the general population?

SYNJ1 p.Phe128= (c.384T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

SYNJ1 p.Phe128=

Q: What condition is associated with SYNJ1 p.Phe128= (c.384T>C)?

SYNJ1 p.Phe128= (c.384T>C) is associated with developmental and epileptic encephalopathy, 53, early-onset Parkinson disease 20 (ClinVar).

c.384T>C · rs746811167 · VCV761446

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

developmental and epileptic encephalopathy, 53

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -2.7, phastCons 1
Overall
CADD	7.619	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,030 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,836 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.Phe128=
Coding: c.384T>C
MANE Select: NM_203446
dbSNP: rs746811167
Type: single nucleotide variant
Location: chr21:32699933 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.09 · 5 PDB
Residue 128: the sac domain

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

Disease context

developmental and epileptic encephalopathy, 53 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: early-onset Parkinson disease 20

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-phe128 (accessed [today's date]).

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