TMEM53

Chr 1AR

transmembrane protein 53

Also known as: CTDI, NET4

NCBI Gene: 79639 ENSG00000126106 UniProt: Q6P2H8 OMIM: 619722

TMEM53 encodes a nuclear membrane protein that regulates bone formation by blocking the nuclear translocation of phosphorylated SMAD1/5/9 proteins, thereby inhibiting BMP signaling in osteoblast cells. Biallelic mutations cause craniotubular dysplasia, Ikegawa type, an autosomal recessive skeletal dysplasia. The gene shows tolerance to loss-of-function variation in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Involved in negative regulation of BMP signaling pathway; negative regulation of ossification; and regulation of nucleocytoplasmic transport. Located in nuclear membrane. Implicated in craniotubular dysplasia Ikegawa type. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.001 OMIM phenotype

Clinical Summary— TMEM53

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 45 VUS of 52 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?

1.00LOEUF

pLI 0.021

Z-score 1.58

OE 0.44 (0.21–1.00)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.01Z-score

OE missense 0.79 (0.69–0.91)

149 obs / 187.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.21–1.00)

0≤0.351.4

Missense OE?0.79 (0.69–0.91)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 4 / 9.1Missense obs/exp: 149 / 187.8Syn Z: 0.83

This gene — mechanism propensity

0.6454th %ile

GOF

0.5857th %ile

LOF

0.2386th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

52 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS45

Likely Benign3

Benign1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	0	0	1	0	1
VUS	0	45	0	0	45
Likely Benign	0	3	0	0	3
Benign	0	0	0	1	1
Total	1	48	1	1	51

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap TMEM53 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →