Is SLC6A3 p.Ala577= (c.1731C>T) pathogenic?

SLC6A3 p.Ala577= (c.1731C>T) is classified Benign in SLC6A3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-27). Common (popmax 8.56%, afr) — too common for a highly-penetrant pathogenic allele; Associated with parkinsonism-dystonia, infantile.

What condition is associated with SLC6A3 p.Ala577= (c.1731C>T)?

SLC6A3 p.Ala577= (c.1731C>T) is associated with parkinsonism-dystonia, infantile (ClinVar).

How is Infantile dystonia-parkinsonism inherited?

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

SLC6A3 p.Ala577=

Q: How common is SLC6A3 p.Ala577= (c.1731C>T) in the general population?

SLC6A3 p.Ala577= (c.1731C>T) is common (popmax 8.56%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1731C>T · rs6349 · VCV287682

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 8.56%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

parkinsonism-dystonia, infantile

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 5.4	GERP 1.6, phastCons 1
Overall
CADD	10.04	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.56% African / African-American · 6,422/75,028 alleles

Filtering AF 8.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.31%

Overall 0.85% 13,721/1,614,000 alleles · common exomes 9,532/1,461,698 · genomes 4,189/152,302 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.56%	12
Ashkenazi Jewishnot grpmax-eligible	4.59%	22
Middle Eastern	1.42%	70
South Asian	1.31%	76
Remaining individualsnot grpmax-eligible	1.26%	79
Admixed American	1.13%	89
European (non-Finnish)	0.263%	380
Finnishnot grpmax-eligible	0.114%	876
East Asian	0.029%	3,453

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: SLC6A3
Protein: p.Ala577=
Coding: c.1731C>T
MANE Select: NM_001044
dbSNP: rs6349
Type: single nucleotide variant
Location: chr5:1402958 (GRCh38)
Gene constraint: LOEUF 0.393 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.58 · 12 PDB
Residue 577: an α-helix; the 'interaction with tgfb1i1' region

Full SLC6A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

parkinsonism-dystonia, infantile — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Infantile dystonia-parkinsonism (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SLC6A3 c.1269+1G>A Pathogenic ★★ same condition
SLC6A3 p.Ala308Val Uncertain significance ★★ ⚠ same condition
SLC6A3 p.Ala346Val Uncertain significance ★★ ⚠ same condition
SLC6A3 p.Ala565Ser Uncertain significance ★★ ⚠ same condition
SLC6A3 p.Arg304Gln Uncertain significance ★★ ⚠ same condition
SLC6A3 p.Arg51Gln Uncertain significance ★★ ⚠ same condition
SLC6A3 p.Arg588Gln Uncertain significance ★★ ⚠ same condition
SLC6A3 p.Arg610His Uncertain significance ★★ ⚠ 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/slc6a3-p-ala577 (accessed [today's date]).

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