Is SLC6A5 p.Ala511= (c.1533C>T) pathogenic?

SLC6A5 p.Ala511= (c.1533C>T) is classified Likely benign in SLC6A5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). Ultra-rare (popmax 0.0107%, afr); Associated with hyperekplexia 3.

What condition is associated with SLC6A5 p.Ala511= (c.1533C>T)?

SLC6A5 p.Ala511= (c.1533C>T) is associated with hyperekplexia 3 (ClinVar).

How common is SLC6A5 p.Ala511= (c.1533C>T) in the general population?

SLC6A5 p.Ala511= (c.1533C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

How is Hereditary hyperekplexia inherited?

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

SLC6A5 p.Ala511=

c.1533C>T · rs368623393 · VCV1624944

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

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 0.82	GERP 1.7, phastCons 1
Overall
CADD	12.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,946 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000867% 14/1,614,102 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,368
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.000339%	295,005

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: SLC6A5
Protein: p.Ala511=
Coding: c.1533C>T
MANE Select: NM_001172501 · reported on NM_004211
dbSNP: rs368623393
Type: single nucleotide variant
Location: chr11:20630724 (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

NET1 p.Glu511Lys Uncertain significance ★ ⚠ same residue
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

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-ala511 (accessed [today's date]).

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