SLC49A4

Chr 3

solute carrier family 49 member 4

Also known as: DIRC2, RCC4

NCBI Gene: 84925 ENSG00000138463 UniProt: Q96SL1 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…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.16

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in SLC49A4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

537 rare PASS variants

Rare truncating (LoF)

1 in 1,700

96 rare PASS variants

Rare synonymous (reference)

1 in 310

269 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SLC49A4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 170	1 in 2,500
South Asian	~43k	1 in 210	1 in 4,600
Remaining (unassigned)	~30k	1 in 97	1 in 1,300
European (Finnish)	~27k	1 in 730	1 in 3,200
Admixed American	~22k	1 in 110	1 in 1,100
African / African American	~21k	1 in 120	1 in 1,400
East Asian	~20k	1 in 130	1 in 2,600
Ashkenazi Jewish	~13k	1 in 1,000	1 in 2,100
Middle Eastern	~2,884	1 in 150	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 8 of 9 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 9.? see exons ↓