Is SYN1 p.Pro656Ser (c.1966C>T) pathogenic?

SYN1 p.Pro656Ser (c.1966C>T) is classified Uncertain significance in SYN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-29). AlphaMissense: likely benign (0.0562); No allele count reported in gnomAD v4.1 (AN 1,148,584); Associated with Inborn genetic diseases.

What condition is associated with SYN1 p.Pro656Ser (c.1966C>T)?

SYN1 p.Pro656Ser (c.1966C>T) is associated with Inborn genetic diseases, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (ClinVar).

How common is SYN1 p.Pro656Ser (c.1966C>T) in the general population?

SYN1 p.Pro656Ser (c.1966C>T) is no allele count reported in gnomAD v4.1 (AN 1,148,584) (gnomAD).

What do computational predictors say about SYN1 p.Pro656Ser (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.0562) — an in-silico prediction, not a clinical call.

SYN1 p.Pro656Ser

c.1966C>T · rs2057768744 · VCV2878805

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0562 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,148,584)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0562	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 1,483 bp · p 0.025 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,148,584). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SYN1
Protein: p.Pro656Ser
Coding: c.1966C>T
MANE Select: NM_006950
dbSNP: rs2057768744
Type: single nucleotide variant
Location: chrX:47574018 (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

Full SYN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

Similar variants

SYN1 p.Pro656Leu Uncertain significance ★★ ⚠ same residue
SYN1 p.Pro656= Benign/Likely benign ★★ 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-pro656ser (accessed [today's date]).

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