SLC34A3

Chr 9AR

solute carrier family 34 member 3

Also known as: HHRH, NPT2C, NPTIIc

NCBI Gene: 142680 ENSG00000198569 UniProt: Q8N130 OMIM: 609826

This gene encodes a sodium-phosphate cotransporter that actively transports phosphate into renal tubular cells via the brush border membrane, maintaining kidney phosphate homeostasis. Mutations cause hypophosphatemic rickets with hypercalciuria, inherited in an autosomal recessive pattern. The gene shows low constraint to loss-of-function variation, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of SLC34A transporter family of proteins, and is expressed primarily in the kidney. It is involved in transporting phosphate into cells via sodium cotransport in the renal brush border membrane, and contributes to the maintenance of inorganic phosphate concentration in the kidney. Mutations in this gene are associated with hereditary hypophosphatemic rickets with hypercalciuria. Alternatively spliced transcript variants varying in the 5' UTR have been found for this gene.[provided by RefSeq, Apr 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.371 OMIM phenotype

Clinical Summary— SLC34A3

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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

98 unique Pathogenic / Likely Pathogenic· 381 VUS of 884 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.37LOEUF

pLI 0.000

Z-score 0.22

OE 0.95 (0.67–1.37)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.29Z-score

OE missense 1.18 (1.10–1.28)

466 obs / 393.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.95 (0.67–1.37)

0≤0.351.4

Missense OE?1.18 (1.10–1.28)

0≤0.61.4

Synonymous OE?1.30

0≤1.21.6

LoF obs/exp: 21 / 22.1Missense obs/exp: 466 / 393.8Syn Z: -3.27

This gene — mechanism propensity

0.76top 25%

GOF

0.74top 25%

LOF

0.3357th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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.

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

ClinVar Variant Classifications

884 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35

Likely Pathogenic63

VUS381

Likely Benign314

Benign25

Conflicting58

Pathogenic

Likely Pathogenic

381

VUS

314

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	29	3	3	0	35
Likely Pathogenic	49	12	1	1	63
VUS	8	331	30	12	381
Likely Benign	0	15	145	154	314
Benign	0	4	16	5	25
Conflicting	—				58
Total	86	365	195	172	876

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

View in ClinVar →

97 pathogenic / likely-pathogenic (of 110) ClinVar copy-number / structural variants overlap SLC34A3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →