Is SLC6A5 p.Phe375= (c.1125C>T) pathogenic?

SLC6A5 p.Phe375= (c.1125C>T) is classified Likely benign in SLC6A5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). Absent from gnomAD v4.1; Associated with hyperekplexia 3.

What condition is associated with SLC6A5 p.Phe375= (c.1125C>T)?

SLC6A5 p.Phe375= (c.1125C>T) is associated with hyperekplexia 3 (ClinVar).

How common is SLC6A5 p.Phe375= (c.1125C>T) in the general population?

SLC6A5 p.Phe375= (c.1125C>T) 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.Phe375=

c.1125C>T · VCV3727446

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 2.8	GERP 0.53, phastCons 1
Overall
CADD	17.36	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.Phe375=
Coding: c.1125C>T
MANE Select: NM_004211
Type: single nucleotide variant
Location: chr11:20614818 (GRCh38)
Structure: AlphaFold pLDDT 87.54 · 36 PDB
Residue 375: a UniProt-annotated variant site (in)

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-phe375 (accessed [today's date]).

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