Is SYN1 p.Thr649= (c.1947C>A) pathogenic?

SYN1 p.Thr649= (c.1947C>A) is classified Likely benign in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-24). Very rare (popmax 0.0036%, afr); Associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

How common is SYN1 p.Thr649= (c.1947C>A) in the general population?

SYN1 p.Thr649= (c.1947C>A) is very rare (popmax 0.0036%, afr) (gnomAD).

SYN1 p.Thr649=

Q: What condition is associated with SYN1 p.Thr649= (c.1947C>A)?

SYN1 p.Thr649= (c.1947C>A) is associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (ClinVar).

Q: How is X-linked epilepsy-learning disabilities-behavior disorders syndrome inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1947C>A · rs747495638 · VCV2861713

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0036%, afr)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Overall
CADD	3.747	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0036% African / African-American · 2/55,481 alleles

Filtering AF 0.000598% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000224%

Overall 0.000521% 6/1,150,565 alleles · very rare exomes 5/1,037,941 · genomes 1/112,624 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0036%	27,740
Admixed American	0.00261%	38,279
European (non-Finnish)	0.000345%	289,831

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.Thr649=
Coding: c.1947C>A
MANE Select: NM_006950
dbSNP: rs747495638
Type: single nucleotide variant
Location: chrX:47574037 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 649: 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

Disease context

epilepsy, X-linked 1, with variable learning disabilities and behavior disorders — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked epilepsy-learning disabilities-behavior disorders syndrome (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood

Similar variants

SYN1 p.Thr649Ile 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
SYN1 p.Gln555Ter 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-thr649 (accessed [today's date]).

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