SLC20A2

Chr 8AD

solute carrier family 20 member 2

Also known as: GLVR-2, GLVR2, IBGC1, IBGC2, IBGC3, MLVAR, PIT-2, PIT2

NCBI Gene: 6575 ENSG00000168575 UniProt: Q08357 OMIM: 158378

The protein functions as a sodium-phosphate symporter that transports phosphate across cell membranes and is critical for maintaining normal cerebrospinal fluid phosphate levels and bone mineralization. Mutations cause familial idiopathic basal ganglia calcification, which follows an autosomal dominant inheritance pattern. The gene is highly constrained against loss-of-function variants (pLI 0.97, LOEUF 0.33), indicating intolerance to haploinsufficiency.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.331 OMIM phenotype

Clinical Summary— SLC20A2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

126 unique Pathogenic / Likely Pathogenic· 212 VUS of 500 total submissions

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GeneReview available — SLC20A2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.33LOEUF

pLI 0.965

Z-score 4.21

OE 0.14 (0.07–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.63Z-score

OE missense 0.63 (0.57–0.70)

261 obs / 411.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.14 (0.07–0.33)

0≤0.351.4

Missense OE0.63 (0.57–0.70)

0≤0.61.4

Synonymous OE1.14

0≤1.21.6

LoF obs/exp: 4 / 28.1Missense obs/exp: 261 / 411.2Syn Z: -1.46

0.6260th %ile

GOF

0.6833th %ile

LOF

0.50top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 53% of P/LP variants are LoF · LOEUF 0.33

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNWe find that in mammalian cells, the analyzed SLC20A2 missense variants can exert their effect in a dominant negative manner resulting in decreased wild-type PiT2 Pi transport.PMID:27943094

LOFOur functional data suggest that these SLC20A2 mutations most likely have an effect through haploinsufficiency rather than by encoding dominant-negative activities.PMID:22327515

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.