TM2D3

Chr 15AR

TM2 domain containing 3

Also known as: BLP2, NCRMS

NCBI Gene: 80213ENSG00000184277UniProt: Q9BRN9

The protein encoded by this gene contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily. This protein has sequence and structural similarities to the beta-amyloid binding protein (BBP), but, unlike BBP, it does not regulate a response to beta-amyloid peptide. This protein may have regulatory roles in cell death or proliferation signal cascades. Several alternatively spliced transcript variants of this gene are described but the full length nature of some variants has not been determined. Multiple polyadenylation sites have been found in this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Neurocardiorenal malformation syndromeMIM #621379
AR
UniProtAlzheimer disease
162
ClinVar variants
78
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TM2D3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
78 Pathogenic / Likely Pathogenic· 58 VUS of 162 total submissions

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

Tolerant to missense variation

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.1.07 (0.68–1.69)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.17 (1.03–1.33)
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.1.28
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
1
2
6
0
9
VUS
0
45
13
0
58
Likely Benign
0
1
14
0
15
Benign
0
0
6
0
6
Total1481080157

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.

Gene2Phenotype Curations

TM2D3-related neurodevelopmental disorder with microcephaly and congenital malformations

moderate
ARLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗
frameshift variantmissense variantstop gained NMD escapingwhole partial gene deletion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurocardiorenal malformation syndrome

MIM #621379

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations.
Loh PR et al.·Nature
2018
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
Functional Studies of Genetic Variants Associated with Human Diseases in Notch Signaling-Related Genes Using Drosophila.
Yang SA et al.·Methods Mol Biol
2022Functional
Fecundity in an infertile man with r(15) - a challenge to the current paradigm.
Kalantari H et al.·Reprod Biomed Online
2018Case report
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
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
Array based characterization of a terminal deletion involving chromosome subband 15q26.2: an emerging syndrome associated with growth retardation, cardiac defects and developmental delay.
Davidsson J et al.·BMC Med Genet
2008Case 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