SLC7A4

Chr 22

solute carrier family 7 member 4

Also known as: CAT-4, CAT4, HCAT3, VH

NCBI Gene: 6545 ENSG00000099960 OMIM: 603752

The SLC7A4 protein transports cationic amino acids including arginine, lysine, and ornithine across cell membranes. Mutations cause autosomal recessive lysinuric protein intolerance, characterized by defective amino acid transport leading to hyperammonemia, failure to thrive, hepatosplenomegaly, and osteoporosis typically presenting in infancy or early childhood. The gene shows tolerance to loss-of-function variants (low constraint), consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable amino acid transmembrane transporter activity. Predicted to be involved in amino acid transport. Predicted to be located in membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.23

Clinical Summary— SLC7A4

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Population Constraint (gnomAD)

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

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ClinVar Variants

120 VUS of 137 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?

1.23LOEUF

pLI 0.000

Z-score 0.90

OE 0.76 (0.48–1.23)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.07Z-score

OE missense 0.99 (0.91–1.08)

393 obs / 397.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.48–1.23)

0≤0.351.4

Missense OE?0.99 (0.91–1.08)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 12 / 15.9Missense obs/exp: 393 / 397.1Syn Z: 0.05

This gene — mechanism propensity

0.80top 25%

GOF

0.78top 25%

LOF

0.2091th %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

137 submitted variants in ClinVar

ClinVar

Classification Summary

VUS120

Likely Benign12

Benign2

120

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	120	0	0	120
Likely Benign	1	9	1	1	12
Benign	0	1	0	1	2
Total	1	130	1	2	134

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

View in ClinVar →

356 pathogenic / likely-pathogenic (of 418) ClinVar copy-number / structural variants overlap SLC7A4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →