SLC46A1

Chr 17

solute carrier family 46 member 1

Also known as: G21, HCP1, HsPCFT, PCFT, hPCFT

NCBI Gene: 113235 ENSG00000076351 UniProt: Q96NT5

This protein functions as a proton-coupled folate transporter that mediates folate absorption in the intestine and transport across the choroid plexus into the central nervous system, and also serves as a heme transporter. Mutations cause autosomal recessive hereditary folate malabsorption, which typically presents in infancy with megaloblastic anemia, developmental delays, and neurological symptoms due to systemic folate deficiency. The gene shows tolerance to loss-of-function variants (LOEUF 0.78), consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transmembrane proton-coupled folate transporter protein that facilitates the movement of folate and antifolate substrates across cell membranes, optimally in acidic pH environments. This protein is also expressed in the brain and choroid plexus where it transports folates into the central nervous system. This protein further functions as a heme transporter in duodenal enterocytes, and potentially in other tissues like liver and kidney. Its localization to the apical membrane or cytoplasm of intestinal cells is modulated by dietary iron levels. Mutations in this gene are associated with autosomal recessive hereditary folate malabsorption disease. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2013]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.78

Clinical Summary— SLC46A1

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 209 VUS of 415 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.022

Z-score 2.14

OE 0.37 (0.19–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.24Z-score

OE missense 0.78 (0.70–0.88)

201 obs / 257.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.19–0.78)

0≤0.351.4

Missense OE?0.78 (0.70–0.88)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 5 / 13.5Missense obs/exp: 201 / 257.2Syn Z: 1.82

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC46A1-related hereditary folate malabsorptionLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.77top 25%

GOF

0.6442th %ile

LOF

0.2190th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

415 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic8

VUS209

Likely Benign130

Benign27

Conflicting15

Pathogenic

Likely Pathogenic

209

VUS

130

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	5	0	0	19
Likely Pathogenic	6	2	0	0	8
VUS	1	140	67	1	209
Likely Benign	0	7	23	100	130
Benign	0	0	27	0	27
Conflicting	—				15
Total	21	154	117	101	408

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap SLC46A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →