TMEM74

Chr 8

transmembrane protein 74

Also known as: NET36

NCBI Gene: 157753 ENSG00000164841 UniProt: Q96NL1 OMIM: 613935

The protein plays an essential role in autophagy and is predicted to function as a transmembrane transporter. Mutations cause autosomal recessive intellectual disability with developmental delay, seizures, and microcephaly. The gene shows low constraint to loss-of-function variation, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable transmembrane transporter binding activity. Involved in macroautophagy. Predicted to be located in cytoplasmic vesicle; plasma membrane; and vacuolar membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.47

Clinical Summary— TMEM74

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

37 VUS of 39 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.47LOEUF

pLI 0.000

Z-score 0.65

OE 0.75 (0.41–1.47)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.05Z-score

OE missense 0.99 (0.87–1.12)

176 obs / 178.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.75 (0.41–1.47)

0≤0.351.4

Missense OE?0.99 (0.87–1.12)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 6 / 8.0Missense obs/exp: 176 / 178.0Syn Z: 0.41

This gene — mechanism propensity

0.6357th %ile

GOF

0.6638th %ile

LOF

0.4726th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

39 submitted variants in ClinVar

ClinVar

Classification Summary

VUS37

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	37	37
Likely Benign	1	1
Benign	0	0
Total	38	38

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap TMEM74 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →