TCIRG1

Chr 11

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: 10312ENSG00000110719UniProt: Q13488

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]

Primary Disease Associations & Inheritance

UniProtOsteopetrosis, autosomal recessive 1
697
ClinVar variants
111
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TCIRG1
🧬
Gene-Disease Validity (ClinGen)
autosomal recessive osteopetrosis 1 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
111 Pathogenic / Likely Pathogenic· 265 VUS of 697 total submissions
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?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.87LOEUF
pLI 0.000
Z-score 2.26
OE 0.63 (0.46–0.87)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.63Z-score
OE missense 0.92 (0.86–0.99)
489 obs / 529.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.63 (0.46–0.87)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.86–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 27 / 43.0Missense obs/exp: 489 / 529.6Syn Z: -0.47

ClinVar Variant Classifications

697 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic54
Likely Pathogenic57
VUS265
Likely Benign311
Benign8
Conflicting2
54
Pathogenic
57
Likely Pathogenic
265
VUS
311
Likely Benign
8
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
34
0
20
0
54
Likely Pathogenic
37
3
17
0
57
VUS
3
232
25
5
265
Likely Benign
0
2
150
159
311
Benign
0
0
8
0
8
Conflicting
—2
Total74237220164697

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

View in ClinVar →

Protein Context — Lollipop Plot

TCIRG1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — TCIRG1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
TCIRG1-associated congenital neutropenia.
Makaryan V et al.·Hum Mutat
2014
Malignant Infantile osteopetrosis.
Vomero A et al.·Rev Chil Pediatr
2019Case report
Osteopetrosis: Gene-based nosology and significance Dysosteosclerosis.
Turan S·Bone
2023
The V-ATPase a3 subunit deficiency affects osteoarthritis via mTOR-Mediated autophagy levels in subchondral bone.
Qiu J et al.·Biochem Pharmacol
2025
[Morphological characteristics of osteopetrosis].
Zustin J et al.·Pathologe
2018Review
Molecular Mechanisms of Craniofacial and Dental Abnormalities in Osteopetrosis.
Ma Y et al.·Int J Mol Sci
2023Review
Whole exome sequencing for identifying rare genetic variants related to idiopathic granulomatous mastitis.
Ozer L et al.·Clin Rheumatol
2025
Outlining the Clinical Profile of TCIRG1 14 Variants including 5 Novels with Overview of ARO Phenotype and Ethnic Impact in 20 Egyptian Families.
El-Kamah GY et al.·Genes (Basel)
2023Review
Clinical presentation and analysis of genotype-phenotype correlations in patients with malignant infantile osteopetrosis.
Even-Or E et al.·Bone
2022Cohort
Case report of mild TCIRG1-associated autosomal recessive osteopetrosis in Vietnam.
Luong LH et al.·Am J Med Genet A
2022Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools