SLC20A2

Chr 8

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

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 ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the inorganic phosphate transporter family. The encoded protein is a type 3 sodium-dependent phosphate symporter that plays an important role in phosphate homeostasis by mediating cellular phosphate uptake. The encoded protein also confers susceptibility to viral infection as a gamma-retroviral receptor. Mutations in this gene may play a role in familial idiopathic basal ganglia calcification. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.33

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

88 unique Pathogenic / Likely Pathogenic· 201 VUS of 451 total submissions

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GeneReview available — SLC20A2

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.14 (0.07–0.33)

0≤0.351.4

Missense OE?0.63 (0.57–0.70)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

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

This gene — mechanism propensity

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 · 76% 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.1

LOFOur functional data suggest that these SLC20A2 mutations most likely have an effect through haploinsufficiency rather than by encoding dominant-negative activities.2

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

References

ClinVar Variant Classifications

451 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic57

Likely Pathogenic31

VUS201

Likely Benign92

Benign39

Conflicting15

Pathogenic

Likely Pathogenic

201

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	51	4	2	0	57
Likely Pathogenic	16	13	2	0	31
VUS	2	162	33	4	201
Likely Benign	0	9	25	58	92
Benign	0	3	29	7	39
Conflicting	—				15
Total	69	191	91	69	435

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap SLC20A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →