SLC49A4

Chr 3

solute carrier family 49 member 4

Also known as: DIRC2, RCC4

NCBI Gene: 84925 ENSG00000138463 OMIM: 602773

This gene encodes a proton-dependent pyridoxine (vitamin B6) transporter that facilitates cellular uptake of this essential vitamin cofactor. Mutations cause autosomal recessive pyridoxine-dependent epilepsy with early infantile onset seizures that are characteristically responsive to pyridoxine supplementation. The gene shows minimal constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a membrane-bound protein from the major facilitator superfamily of transporters. Disruption of this gene by translocation has been associated with haplo-insufficiency and renal cell carcinomas. Alternatively spliced transcript variants have been described, but their biological validity has not yet been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.16

Clinical Summary— SLC49A4

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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

59 VUS of 79 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?

1.16LOEUF

pLI 0.000

Z-score 1.01

OE 0.76 (0.51–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.32Z-score

OE missense 0.76 (0.68–0.86)

188 obs / 246.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.51–1.16)

0≤0.351.4

Missense OE?0.76 (0.68–0.86)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 16 / 21.0Missense obs/exp: 188 / 246.5Syn Z: 0.45

This gene — mechanism propensity

0.7132th %ile

GOF

0.72top 25%

LOF

0.2580th %ile

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

GOFprediction above median

DNprediction 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

79 submitted variants in ClinVar

ClinVar

Classification Summary

VUS59

Likely Benign1

Benign2

Conflicting1

VUS

Likely Benign

Benign

Conflicting

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	59	0	0	59
Likely Benign	0	1	0	0	1
Benign	0	2	0	0	2
Conflicting	—				1
Total	0	62	0	0	63

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap SLC49A4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →