SLC10A2

Chr 13

solute carrier family 10 member 2

Also known as: ASBT, IBAT, ISBT, NTCP2, PBAM, PBAM1

NCBI Gene: 6555 ENSG00000125255 UniProt: Q12908

This protein is a sodium/bile acid cotransporter that mediates reabsorption of bile acids in the distal ileum and renal proximal tubules, playing a critical role in enterohepatic circulation and cholesterol homeostasis. Mutations cause primary bile acid malabsorption, an autosomal recessive disorder affecting the gastrointestinal system. The gene shows high tolerance to loss-of-function variants (LOEUF 1.944), consistent with the recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a sodium/bile acid cotransporter. This transporter is the primary mechanism for uptake of intestinal bile acids by apical cells in the distal ileum. Bile acids are the catabolic product of cholesterol metabolism, so this protein is also critical for cholesterol homeostasis. Mutations in this gene cause primary bile acid malabsorption (PBAM); muatations in this gene may also be associated with other diseases of the liver and intestines, such as familial hypertriglyceridemia (FHTG). [provided by RefSeq, Mar 2010]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.94

Clinical Summary— SLC10A2

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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

2 unique Pathogenic / Likely Pathogenic· 268 VUS of 419 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?

1.94LOEUF

pLI 0.000

Z-score -2.02

OE 1.62 (1.11–1.94)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.20Z-score

OE missense 1.43 (1.30–1.58)

292 obs / 203.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.62 (1.11–1.94)

0≤0.351.4

Missense OE?1.43 (1.30–1.58)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 20 / 12.4Missense obs/exp: 292 / 203.5Syn Z: -0.98

This gene — mechanism propensity

0.74top 25%

GOF

0.79top 25%

LOF

0.2191th %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

419 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS268

Likely Benign105

Benign14

Conflicting28

Pathogenic

Likely Pathogenic

268

VUS

105

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	1	0	0	0	1
VUS	30	222	14	2	268
Likely Benign	0	6	34	65	105
Benign	0	3	8	3	14
Conflicting	—				28
Total	31	232	56	70	417

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

View in ClinVar →

102 pathogenic / likely-pathogenic (of 112) ClinVar copy-number / structural variants overlap SLC10A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →