Is SYN1 p.Ala304= (c.912C>T) pathogenic?

SYN1 p.Ala304= (c.912C>T) is classified Benign in SYN1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Low-frequency (popmax 4.6%, afr); Associated with History of neurodevelopmental disorder.

What condition is associated with SYN1 p.Ala304= (c.912C>T)?

SYN1 p.Ala304= (c.912C>T) is associated with History of neurodevelopmental disorder, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (ClinVar).

How common is SYN1 p.Ala304= (c.912C>T) in the general population?

SYN1 p.Ala304= (c.912C>T) is low-frequency (popmax 4.6%, afr) (gnomAD).

SYN1 p.Ala304=

c.912C>T · rs62636605 · VCV130386

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.6%, afr)

Conditions

History of neurodevelopmental disorder

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 -9.2
Overall
CADD	0.409	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.6% African / African-American · 2,627/57,087 alleles

Filtering AF 4.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.4%

Overall 0.26% 3,146/1,210,006 alleles · low-frequency exomes 1,659/1,098,231 · genomes 1,487/111,775 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.6%	22
Remaining individualsnot grpmax-eligible	0.517%	194
Admixed American	0.397%	252
Middle Eastern	0.299%	334
South Asian	0.0387%	2,583
European (non-Finnish)	0.00603%	16,579
Finnishnot grpmax-eligible	0.00429%	23,294

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.Ala304=
Coding: c.912C>T
MANE Select: NM_006950
dbSNP: rs62636605
Type: single nucleotide variant
Location: chrX:47576566 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 304: the 'c; actin-binding and synaptic-vesicle binding' region

Full SYN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

History of neurodevelopmental disorder — 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.Ala304Thr 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-ala304 (accessed [today's date]).

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