Is SYN1 p.Arg507Ser (c.1519C>A) pathogenic?

SYN1 p.Arg507Ser (c.1519C>A) is classified Uncertain significance in SYN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: ambiguous (0.5395); Very rare (popmax 0.00192%, afr); Associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

What condition is associated with SYN1 p.Arg507Ser (c.1519C>A)?

SYN1 p.Arg507Ser (c.1519C>A) is associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (ClinVar).

How common is SYN1 p.Arg507Ser (c.1519C>A) in the general population?

SYN1 p.Arg507Ser (c.1519C>A) is very rare (popmax 0.00192%, afr) (gnomAD).

What do computational predictors say about SYN1 p.Arg507Ser (c.1519C>A)?

AlphaMissense predicts ambiguous (score 0.5395) — an in-silico prediction, not a clinical call.

SYN1 p.Arg507Ser

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.1519C>A · rs2057770942 · VCV1419896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00192%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5395	ambiguous
REVEL	0.072	moderately benign-leaning
SaProt	LLR -8.60	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 45 kb · p 1.4e-10 · regional, not allelic
Overall
CADD	22.8	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

Grpmax group 0.00192% African / African-American · 1/52,005 alleles

Filtering AF 4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.5e-05%

Overall 0.00028% 3/1,070,368 alleles · very rare exomes 2/959,293 · genomes 1/111,075 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00192%	52,005
European (non-Finnish)	0.00024%	416,924

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.Arg507Ser
Coding: c.1519C>A
MANE Select: NM_006950
dbSNP: rs2057770942
Type: single nucleotide variant
Location: chrX:47574465 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 507: 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 p.Arg507Leu 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-arg507ser (accessed [today's date]).

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