SLC45A4

Chr 8

solute carrier family 45 member 4

NCBI Gene: 57210 ENSG00000022567 UniProt: Q5BKX6 OMIM: 619581

The SLC45A4 protein is a neuronal polyamine transporter that transports putrescine, cadaverine, spermine and spermidine in sensory neurons within the dorsal root ganglion, where it regulates the excitability of pain-sensing C-polymodal nociceptors. This gene is highly intolerant to loss-of-function variants (pLI nearly 1.0) but no established human disease associations have been reported to date. The inheritance pattern for potential SLC45A4-related disorders would be expected to be autosomal recessive given the high constraint against heterozygous loss-of-function.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable sucrose:proton symporter activity. Predicted to be involved in sucrose transport. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.71

Clinical Summary— SLC45A4

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

83 VUS of 93 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 2.67

OE 0.43 (0.27–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.83Z-score

OE missense 0.90 (0.83–0.97)

486 obs / 540.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.27–0.71)

0≤0.351.4

Missense OE?0.90 (0.83–0.97)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 11 / 25.5Missense obs/exp: 486 / 540.5Syn Z: -1.41

This gene — mechanism propensity

0.78top 25%

GOF

0.7125th %ile

LOF

0.2777th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

93 submitted variants in ClinVar

ClinVar

Classification Summary

VUS83

Likely Benign10

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	83	0	83
Likely Benign	8	2	10
Benign	0	0	0
Total	91	2	93

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

6 pathogenic / likely-pathogenic (of 7) ClinVar copy-number / structural variants overlap SLC45A4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →