Is SYN1 p.Pro518= (c.1554C>T) pathogenic?

SYN1 p.Pro518= (c.1554C>T) is classified Likely benign in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). Very rare (popmax 0.00403%, afr); Associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

How common is SYN1 p.Pro518= (c.1554C>T) in the general population?

SYN1 p.Pro518= (c.1554C>T) is very rare (popmax 0.00403%, afr) (gnomAD).

SYN1 p.Pro518=

Q: What condition is associated with SYN1 p.Pro518= (c.1554C>T)?

SYN1 p.Pro518= (c.1554C>T) 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.1554C>T · rs1344835504 · VCV3012616

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00403%, 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; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.37
Overall
CADD	5.247	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00403% African / African-American · 2/49,628 alleles

Filtering AF 0.000668% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00025%

Overall 0.000193% 2/1,034,428 alleles · very rare exomes 1/922,757 · genomes 1/111,671 · joint denominator

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.Pro518=
Coding: c.1554C>T
MANE Select: NM_006950
dbSNP: rs1344835504
Type: single nucleotide variant
Location: chrX:47574430 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 518: the 'disordered' region; 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 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
SYN1 p.Glu121Ter Pathogenic/Likely 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-pro518 (accessed [today's date]).

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