Is SLC6A5 p.Pro756= (c.2268G>A) pathogenic?

SLC6A5 p.Pro756= (c.2268G>A) is classified Likely benign in SLC6A5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). Ultra-rare (popmax 0.0133%, afr); Associated with hyperekplexia 3.

What condition is associated with SLC6A5 p.Pro756= (c.2268G>A)?

SLC6A5 p.Pro756= (c.2268G>A) is associated with hyperekplexia 3 (ClinVar).

How common is SLC6A5 p.Pro756= (c.2268G>A) in the general population?

SLC6A5 p.Pro756= (c.2268G>A) is ultra-rare (popmax 0.0133%, 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.Pro756=

c.2268G>A · rs373204248 · VCV757477

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Conditions

hyperekplexia 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.4	GERP -5.3
Overall
CADD	1.023	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/75,048 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00118% 19/1,614,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,505
Remaining individualsnot grpmax-eligible	0.0032%	31,250
Finnishnot grpmax-eligible	0.00156%	64,034
European (non-Finnish)	0.000508%	196,669

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.Pro756=
Coding: c.2268G>A
MANE Select: NM_001172501 · reported on NM_004211
dbSNP: rs373204248
Type: single nucleotide variant
Location: chr11:20654742 (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 p.Pro756Leu 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-pro756 (accessed [today's date]).

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