Is SYN1 p.Ala523= (c.1569G>A) pathogenic?

SYN1 p.Ala523= (c.1569G>A) is classified Conflicting classifications of pathogenicity in SYN1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.0272%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SYN1 p.Ala523= (c.1569G>A)?

SYN1 p.Ala523= (c.1569G>A) is associated with Inborn genetic diseases, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (ClinVar).

How common is SYN1 p.Ala523= (c.1569G>A) in the general population?

SYN1 p.Ala523= (c.1569G>A) is ultra-rare (popmax 0.0272%, nfe) (gnomAD).

SYN1 p.Ala523=

c.1569G>A · rs587781185 · VCV139383

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0272%, nfe)

Conditions

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 -0.61	phastCons 0.02
Overall
CADD	5.442	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0272% European (non-Finnish) · 221/812,815 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.0238% 244/1,026,253 alleles · ultra-rare exomes 221/914,813 · genomes 23/111,440 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0431%	2,318
Remaining individualsnot grpmax-eligible	0.0276%	3,620
European (non-Finnish)grpmax	0.0272%	3,678

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala523=
Coding: c.1569G>A
MANE Select: NM_006950
dbSNP: rs587781185
Type: single nucleotide variant
Location: chrX:47574415 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 523: 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

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.Ala523Val 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-ala523 (accessed [today's date]).

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