Is SYN1 p.Ala550fs (c.1647_1650del) pathogenic?

SYN1 p.Ala550fs (c.16471650del) is classified Pathogenic in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). Very rare (popmax 0.000606%, nfe); Associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

What condition is associated with SYN1 p.Ala550fs (c.1647_1650del)?

SYN1 p.Ala550fs (c.1647_1650del) is associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (ClinVar).

How common is SYN1 p.Ala550fs (c.1647_1650del) in the general population?

SYN1 p.Ala550fs (c.1647_1650del) is very rare (popmax 0.000606%, nfe) (gnomAD).

SYN1 p.Ala550fs

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.1647_1650del · rs1456167867 · VCV2133546

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000606%, nfe)

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.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 12 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.3	phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000606% European (non-Finnish) · 5/825,508 alleles

Filtering AF 0.000177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000129%

Overall 0.000569% 6/1,055,089 alleles · very rare exomes 6/943,618 · genomes 0/111,471 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00337%	29,706
European (non-Finnish)grpmax	0.000606%	165,102

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.Ala550fs
Coding: c.1647_1650del
MANE Select: NM_006950
dbSNP: rs1456167867
Type: Microsatellite
Location: chrX:47574334 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 550: the 'disordered' region; a UniProt-annotated variant site (in xlid50; uncertain significance; no effect on phosphorylation by camk2 and mapk1; has no effect on axon elongation when tested in syn1-knockout mouse neurons; slightly reduced 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.Ala550Phe Uncertain significance ★ same residue
SYN1 p.Ala550Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
SYN1 p.Ala650fs Pathogenic ★ same condition
SYN1 c.684+5_684+8del Uncertain significance ★ same condition
SYN1 p.Gln491del Conflicting classifications of pathogenicity ★ same condition
SYN1 p.Ser551fs Conflicting classifications of pathogenicity ★ ⚠ same condition
SYN1 c.1394-18_1394-15del Likely benign ★ same condition
SYN1 c.528-2A>T 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-ala550fs (accessed [today's date]).

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