Is SLC6A8 p.Pro554= (c.1662G>A) pathogenic?

SLC6A8 p.Pro554= (c.1662G>A) is classified Benign/Likely benign in SLC6A8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0451%, nfe); Associated with creatine transporter deficiency.

What condition is associated with SLC6A8 p.Pro554= (c.1662G>A)?

SLC6A8 p.Pro554= (c.1662G>A) is associated with creatine transporter deficiency (ClinVar).

How common is SLC6A8 p.Pro554= (c.1662G>A) in the general population?

SLC6A8 p.Pro554= (c.1662G>A) is ultra-rare (popmax 0.0451%, nfe) (gnomAD).

How is X-linked creatine transporter deficiency inherited?

Typically Not applicable, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SLC6A8 p.Pro554=

c.1662G>A · rs149677083 · VCV383258

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0451%, nfe)

Conditions

creatine transporter deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.3	GERP -3.8
Overall
CADD	0.311	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0451% European (non-Finnish) · 403/893,765 alleles

Filtering AF 0.0414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.0343% 414/1,208,341 alleles · ultra-rare exomes 403/1,095,464 · genomes 11/112,877 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0451%	2,218
Remaining individualsnot grpmax-eligible	0.0105%	9,498
Admixed American	0.00652%	15,327
African / African-American	0.00348%	28,723
South Asian	0.00176%	56,807

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: SLC6A8
Protein: p.Pro554=
Coding: c.1662G>A
MANE Select: NM_005629
dbSNP: rs149677083
Type: single nucleotide variant
Location: chrX:153694784 (GRCh38)
Structure: AlphaFold pLDDT 85.63 · 6 PDB
Residue 554: a UniProt-annotated variant site (in ccds1; decreased creatine transporter activity)

Full SLC6A8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

creatine transporter deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked creatine transporter deficiency (Orphanet):

Inheritance: Not applicable, X-linked recessive
Onset: Childhood, Infancy

Similar variants

SLC6A8 p.Pro554Leu Pathogenic ★★★ same residue
SLC6A8 c.1016+2T>C Pathogenic ★★★ same condition
SLC6A8 c.1142-2A>G Likely pathogenic ★★★ same condition
SLC6A8 c.1495+2T>G Pathogenic ★★★ same condition
SLC6A8 c.1495+5G>C Pathogenic ★★★ same condition
SLC6A8 c.262+1G>T Pathogenic ★★★ same condition
SLC6A8 c.263-1G>C Pathogenic ★★★ same condition
SLC6A8 c.263-2A>G 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/slc6a8-p-pro554 (accessed [today's date]).

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