Is SLC6A5 p.Phe683= (c.2049T>C) pathogenic?

SLC6A5 p.Phe683= (c.2049T>C) is classified Likely benign in SLC6A5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-17). Absent from gnomAD v4.1; Associated with hyperekplexia 3.

What condition is associated with SLC6A5 p.Phe683= (c.2049T>C)?

SLC6A5 p.Phe683= (c.2049T>C) is associated with hyperekplexia 3 (ClinVar).

How common is SLC6A5 p.Phe683= (c.2049T>C) in the general population?

SLC6A5 p.Phe683= (c.2049T>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary hyperekplexia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SLC6A5 p.Phe683=

c.2049T>C · VCV4807884

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hyperekplexia 3

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 -0.43	GERP -4.7, phastCons 0.087
Overall
CADD	7.469	PHRED · no single calibrated threshold — expert panels disagree

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: SLC6A5
Protein: p.Phe683=
Coding: c.2049T>C
MANE Select: NM_001172501 · reported on NM_004211
Type: single nucleotide variant
Location: chr11:20646913 (GRCh38)
Structure: AlphaFold pLDDT 87.54 · 36 PDB

Full SLC6A5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hyperekplexia 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary hyperekplexia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SLC6A5 c.2070+1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC6A5 c.679+1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC6A5 c.985+1G>A Likely pathogenic ★★ same condition
SLC6A5 p.Arg191Ter Pathogenic ★★ same condition
SLC6A5 p.Arg439Ter Pathogenic ★★ same condition
SLC6A5 p.Cys3Ter Pathogenic/Likely pathogenic ★★ same condition
SLC6A5 p.Phe547Ser Pathogenic/Likely pathogenic ★★ same condition
SLC6A5 p.Pro243Thr 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/slc6a5-p-phe683 (accessed [today's date]).

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