SYN1 p.Pro656=
c.1968G>A · rs199844514 · VCV207464
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
rare (popmax 0.243%, eas)
Conditions
2
Inborn genetic diseases
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 -2.3 | |
| Overall | ||
| CADD | 6.27 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.243%
East Asian · 72/29,653 alleles
Filtering AF
0.198%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.181%
Overall
0.0115%
132/1,144,087 alleles · rare
exomes 110/1,031,563 · genomes 22/112,524 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.243% | 412 |
| Remaining individualsnot grpmax-eligible | 0.093% | 1,076 |
| Middle Eastern | 0.0328% | 3,046 |
| South Asian | 0.0236% | 4,245 |
| Admixed American | 0.00535% | 18,701 |
| European (non-Finnish) | 0.000346% | 289,068 |
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
- SYN1
- Protein
- p.Pro656=
- Coding
- c.1968G>A
- MANE Select
- NM_006950
- dbSNP
- rs199844514
- Type
- single nucleotide variant
- Location
- chrX:47574016 (GRCh38)
- Structure
- AlphaFold pLDDT 69.86
- Residue 656
- the 'disordered' region; a UniProt-annotated variant site (in xlid50; affects excitatory and inhibitory synaptic transmission leading to neuronal hyperexcitability; fails to rescue defective synaptic vesicle exocytosis in syn1-knockout mouse neurons; results in severely decreased phosphorylation by camk2 and mapk1; results in delayed axon elongation when tested in syn1-knockout mouse neurons; severely reduced interaction with syn2; has no effect on protein targeting to presynapse); the 'e' region
Similar variants
- SYN1 p.Pro656Leu Uncertain significance ★★ ⚠ same residue
- SYN1 p.Pro656Ser Uncertain significance ★★ ⚠ same residue
- SYN1 c.528-2A>T Pathogenic/Likely pathogenic ★★ same condition
- SYN1 c.838-2A>G Likely pathogenic ★★ same condition
- SYN1 p.Arg234Ter Pathogenic ★★ same condition
- SYN1 p.Arg420Gln Likely pathogenic ★★ ⚠ same condition
- SYN1 p.Arg422Ter Pathogenic ★★ same condition
- SYN1 p.Gln483Ter Pathogenic ★★ 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/syn1-p-pro656 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown