Is SYN1 p.Arg565Cys (c.1693C>T) pathogenic?

SYN1 p.Arg565Cys (c.1693C>T) is classified Uncertain significance in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: ambiguous (0.4655); No allele count reported in gnomAD v4.1 (AN 1,101,621).

How common is SYN1 p.Arg565Cys (c.1693C>T) in the general population?

SYN1 p.Arg565Cys (c.1693C>T) is no allele count reported in gnomAD v4.1 (AN 1,101,621) (gnomAD).

What do computational predictors say about SYN1 p.Arg565Cys (c.1693C>T)?

AlphaMissense predicts ambiguous (score 0.4655) — an in-silico prediction, not a clinical call.

SYN1 p.Arg565Cys

c.1693C>T · VCV3361699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4655 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,101,621)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4655	ambiguous
REVEL	0.236	benign-leaning
SaProt	LLR -14.19	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 1,483 bp · p 0.025 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

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 1,101,621). 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.Arg565Cys
Coding: c.1693C>T
MANE Select: NM_006950
Type: single nucleotide variant
Location: chrX:47574291 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 565: 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 'd; pro-rich linker' region

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

Similar variants

SYN1 p.Arg565Gly Uncertain significance ★ ⚠ same residue
SYN1 c.528-2A>T Pathogenic/Likely pathogenic ★★ same type
SYN1 c.838-2A>G Likely pathogenic ★★ same type
SYN1 p.Arg234Ter Pathogenic ★★ same type
SYN1 p.Arg420Gln Likely pathogenic ★★ ⚠ same type
SYN1 p.Arg422Ter Pathogenic ★★ same type
SYN1 p.Gln249Ter Pathogenic/Likely pathogenic ★★ same type
SYN1 p.Gln483Ter Pathogenic ★★ same type

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-arg565cys (accessed [today's date]).

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