TMEM106B

Chr 7

transmembrane protein 106B

Also known as: HLD16

NCBI Gene: 54664 ENSG00000106460 UniProt: Q9NUM4

The protein regulates lysosomal transport and acidification in neurons, particularly affecting the movement of late endosomes/lysosomes and dendrite morphogenesis. Mutations cause hypomyelinating leukodystrophy 16, inherited in an autosomal dominant pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.604), suggesting some tolerance to haploinsufficiency while still being associated with neurological disease.

ResearchSummary from RefSeq, OMIM, UniProt

Enables ATPase binding activity. Involved in dendrite morphogenesis and lysosome localization. Located in endosome and lysosomal membrane. Implicated in hypomyelinating leukodystrophy 16. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.60

Clinical Summary— TMEM106B

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Gene-Disease Validity (ClinGen)

leukodystrophy, hypomyelinating, 16 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 65 VUS of 133 total submissions

Explore recent and relevant literature in Research Assistant →

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?

0.60LOEUF

pLI 0.326

Z-score 2.55

OE 0.23 (0.10–0.60)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.92Z-score

OE missense 0.79 (0.68–0.92)

115 obs / 146.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.10–0.60)

0≤0.351.4

Missense OE?0.79 (0.68–0.92)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 3 / 12.8Missense obs/exp: 115 / 146.2Syn Z: -0.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTMEM106B related hypomyelinating leukodystrophyOTHERAD

This gene — mechanism propensity

0.5378th %ile

GOF

0.5661th %ile

LOF

0.4233th %ile

The Badonyi & Marsh model scores gain-of-function highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation

Literature Evidence

LOFTogether, these data raise the possibility that reduction of TMEM106B levels may protect against the pathogenic effects of progranulin haploinsufficiency.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 29929528 ↗

ClinVar Variant Classifications

133 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS65

Likely Benign33

Benign12

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	1	0	0	1
VUS	3	56	4	2	65
Likely Benign	0	7	11	15	33
Benign	0	3	6	3	12
Conflicting	—				4
Total	3	68	21	20	116

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap TMEM106B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →