TCIRG1

Chr 11AR

T cell immune regulator 1, ATPase H+ transporting V0 subunit a3

Also known as: ATP6N1C, ATP6V0A3, Atp6i, OC-116kDa, OC116, OPTB1, Stv1, TIRC7

NCBI Gene: 10312 ENSG00000110719 UniProt: Q13488 OMIM: 604592

This protein is a subunit of the vacuolar H+-ATPase complex that pumps protons across membranes to regulate cellular and extracellular pH, which is essential for processes like protein sorting and receptor-mediated endocytosis. Mutations cause autosomal recessive infantile malignant osteopetrosis, a severe bone disease with early onset that affects bone resorption and can involve immune dysfunction. The gene shows very low constraint against loss-of-function variants in the general population.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a subunit of a large protein complex known as a vacuolar H+-ATPase (V-ATPase). The protein complex acts as a pump to move protons across the membrane. This movement of protons helps regulate the pH of cells and their surrounding environment. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. V-ATPase is comprised of a cytosolic V1 domain and a transmembrane V0 domain. Alternative splicing results in multiple transcript variants. Mutations in this gene are associated with infantile malignant osteopetrosis. [provided by RefSeq, May 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.871 OMIM phenotype

Clinical Summary— TCIRG1

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Gene-Disease Validity (ClinGen)

autosomal recessive osteopetrosis 1 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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

286 unique Pathogenic / Likely Pathogenic· 615 VUS of 1790 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TCIRG1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.26

OE 0.63 (0.46–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.63Z-score

OE missense 0.92 (0.86–0.99)

489 obs / 529.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.46–0.87)

0≤0.351.4

Missense OE?0.92 (0.86–0.99)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 27 / 43.0Missense obs/exp: 489 / 529.6Syn Z: -0.47

This gene — mechanism propensity

0.78top 25%

GOF

0.81top 10%

LOF

0.1895th %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

1790 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic104

Likely Pathogenic182

VUS615

Likely Benign782

Benign26

Conflicting69

104

Pathogenic

182

Likely Pathogenic

615

VUS

782

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	96	2	6	0	104
Likely Pathogenic	161	13	7	1	182
VUS	6	544	44	21	615
Likely Benign	1	12	311	458	782
Benign	0	4	20	2	26
Conflicting	—				69
Total	264	575	388	482	1,778

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap TCIRG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →