TM2D3

Chr 15AR

TM2 domain containing 3

Also known as: BLP2, NCRMS

NCBI Gene: 80213ENSG00000184277UniProt: Q9BRN9OMIM: 610014

TM2D3 encodes a probable positive regulator of Notch signaling with structural similarity to G protein-coupled receptors. Biallelic mutations cause neurocardiorenal malformation syndrome, an autosomal recessive disorder affecting the nervous system, heart, and kidneys. The gene is highly constrained against loss-of-function variation (pLI near 0, LOEUF 1.69), indicating intolerance to functional disruption.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 1.691 OMIM phenotype
Clinical Summary— TM2D3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
78 unique Pathogenic / Likely Pathogenic· 58 VUS of 162 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
1.69LOEUF
pLI 0.000
Z-score -0.22
OE 1.07 (0.68–1.69)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.74Z-score
OE missense 1.17 (1.03–1.33)
174 obs / 148.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE1.07 (0.68–1.69)
0≤0.351.4
Missense OE1.17 (1.03–1.33)
0≤0.61.4
Synonymous OE1.28
0≤1.21.6
LoF obs/exp: 12 / 11.2Missense obs/exp: 174 / 148.5Syn Z: -1.68

ClinVar Variant Classifications

162 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69
Likely Pathogenic9
VUS58
Likely Benign15
Benign6
69
Pathogenic
9
Likely Pathogenic
58
VUS
15
Likely Benign
6
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
69
0
69
Likely Pathogenic
2
2
5
0
9
VUS
0
45
13
0
58
Likely Benign
0
1
14
0
15
Benign
0
0
6
0
6
Total2481070157

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

View in ClinVar →

Protein Context — Lollipop Plot

TM2D3 · 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.

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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
Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities.
Gabillard-Lefort C et al.·Am J Hum Genet
2025
Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
Jakobsdottir J et al.·PLoS Genet
2016Functional
Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles.
Cochran JN et al.·Cold Spring Harb Mol Case Stud
2019
Microdeletion 15q26.2qter and Microduplication 18q23 in a Patient with Prader-Willi-Like Syndrome: Clinical Findings.
Dello Russo P et al.·Cytogenet Genome Res
2016Case report
Functional Studies of Genetic Variants Associated with Human Diseases in Notch Signaling-Related Genes Using Drosophila.
Yang SA et al.·Methods Mol Biol
2022Functional
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