Is SYNJ1 p.Val742= (c.2226T>A) pathogenic?

SYNJ1 p.Val742= (c.2226T>A) is classified Benign/Likely benign in SYNJ1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). Rare (popmax 0.329%, sas); Associated with developmental and epileptic encephalopathy, 53.

How common is SYNJ1 p.Val742= (c.2226T>A) in the general population?

SYNJ1 p.Val742= (c.2226T>A) is rare (popmax 0.329%, sas) (gnomAD).

SYNJ1 p.Val742=

Q: What condition is associated with SYNJ1 p.Val742= (c.2226T>A)?

SYNJ1 p.Val742= (c.2226T>A) is associated with developmental and epileptic encephalopathy, 53, early-onset Parkinson disease 20 (ClinVar).

c.2226T>A · rs566533509 · VCV544573

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.329%, sas)

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 0.45	GERP -3.7, phastCons 0.85
Overall
CADD	5.827	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.329% South Asian · 300/91,048 alleles

Filtering AF 0.299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.287%

Overall 0.02% 322/1,613,798 alleles · rare exomes 309/1,461,512 · genomes 13/152,286 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.329%	303
Remaining individualsnot grpmax-eligible	0.0208%	4,807
Middle Eastern	0.0165%	6,056
African / African-American	0.00533%	18,755
European (non-Finnish)	0.000339%	294,957

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.Val742=
Coding: c.2226T>A
MANE Select: NM_203446
dbSNP: rs566533509
Type: single nucleotide variant
Location: chr21:32664991 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.09 · 5 PDB
Residue 742: the 5-ppase domain; an α-helix

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-val742 (accessed [today's date]).

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