TMEM38B

Chr 9AR

transmembrane protein 38B

Also known as: C9orf87, D4Ertd89e, OI14, TRIC-B, TRICB, bA219P18.1

NCBI Gene: 55151ENSG00000095209UniProt: Q9NVV0OMIM: 611236

This gene encodes an intracellular monovalent cation channel that maintains rapid intracellular calcium release by acting as a potassium counter-ion channel synchronized with calcium release from intracellular stores. Mutations cause osteogenesis imperfecta type XIV with autosomal recessive inheritance. The gene shows tolerance to loss-of-function variants (pLI 0.02, LOEUF 0.80), consistent with the recessive inheritance pattern.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismARLOEUF 0.801 OMIM phenotype
Clinical Summary— TMEM38B
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
63 unique Pathogenic / Likely Pathogenic· 100 VUS of 281 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — TMEM38B
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
0.80LOEUF
pLI 0.020
Z-score 2.09
OE 0.38 (0.20–0.80)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
-0.05Z-score
OE missense 1.01 (0.89–1.15)
158 obs / 156.2 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.38 (0.20–0.80)
0≤0.351.4
Missense OE1.01 (0.89–1.15)
0≤0.61.4
Synonymous OE1.14
0≤1.21.6
LoF obs/exp: 5 / 13.2Missense obs/exp: 158 / 156.2Syn Z: -0.84
DN
0.7035th %ile
GOF
0.6541th %ile
LOF
0.3165th %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

281 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic54
Likely Pathogenic9
VUS100
Likely Benign80
Benign21
Conflicting8
54
Pathogenic
9
Likely Pathogenic
100
VUS
80
Likely Benign
21
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
49
0
54
Likely Pathogenic
6
0
3
0
9
VUS
2
80
17
1
100
Likely Benign
0
2
37
41
80
Benign
0
2
18
1
21
Conflicting
—8
Total138412443272

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEM38B · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Mineralised bone properties in a child with recessive osteogenesis imperfecta type XIV and in a conditional Tmem38b knockout murine model (Runx2-Cre; Tmem38b(fl/fl)).
Jones CE et al.·Bone
2025Functional
Previously Unreported TMEM38B Variant in Osteogenesis Imperfecta Type XIV: A Case Report and Systematic Review of the Literature.
Zoller T et al.·Int J Mol Sci
2025Case report
Two novel mutations in TMEM38B result in rare autosomal recessive osteogenesis imperfecta.
Lv F et al.·J Hum Genet
2016
Osteogenesis imperfecta in 140 Turkish families: Molecular spectrum and, comparison of long-term clinical outcome of those with COL1A1/A2 and biallelic variants.
Tüysüz B et al.·Bone
2022
Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect.
Webb EA et al.·J Clin Endocrinol Metab
2017
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients