Is SYN1 p.Arg5Gln (c.14G>A) pathogenic?

SYN1 p.Arg5Gln (c.14G>A) is classified Uncertain significance in SYN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.993); Absent from gnomAD v4.1; Associated with epilepsy, X-linked 1, with variable learning disabilities and behavior disorders.

How common is SYN1 p.Arg5Gln (c.14G>A) in the general population?

SYN1 p.Arg5Gln (c.14G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SYN1 p.Arg5Gln (c.14G>A)?

AlphaMissense predicts likely pathogenic (score 0.993) — an in-silico prediction, not a clinical call.

SYN1 p.Arg5Gln

Q: What condition is associated with SYN1 p.Arg5Gln (c.14G>A)?

SYN1 p.Arg5Gln (c.14G>A) 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.14G>A · VCV3722207

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.993	likely pathogenic
REVEL	0.217	benign-leaning
SaProt	LLR -12.32	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 45 kb · p 1.4e-10 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SYN1
Protein: p.Arg5Gln
Coding: c.14G>A
MANE Select: NM_006950
Type: single nucleotide variant
Location: chrX:47619715 (GRCh38)
Structure: AlphaFold pLDDT 69.86
Residue 5: the 'disordered' region; the 'a' 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.Arg5Gly 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-arg5gln (accessed [today's date]).

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