MUC4

Chr 3

mucin 4, cell surface associated

ENSG00000145113 UniProt: Q99102 OMIM: 158372

This protein is a membrane-bound mucin that forms the major component of mucus covering epithelial surfaces and regulates epithelial cell proliferation and differentiation through interactions with ERBB2 receptor signaling. The gene is extremely tolerant to loss-of-function variants in the general population, and pathogenic variants have not been established to cause human disease. MUC4 contains highly variable tandem repeat regions that complicate genetic analysis and may contribute to its apparent tolerance to sequence variation.

OMIM ResearchSummary from RefSeq, UniProt

Membrane-bound mucin, a family of highly glycosylated proteins that constitute the major component of the mucus, the slimy and viscous secretion covering epithelial surfaces (PubMed:10880978). These glycoproteins play important roles in the protection of the epithelium and are implicated in epithelial renewal and differentiation (PubMed:10880978). Regulates cellular behavior through both anti-adhesive effects on cell-cell and cell-extracellular matrix interactions and its ability to act as an intramembrane ligand for ERBB2. Plays an important role in proliferation and differentiation of epithelial cells by inducing specific phosphorylation of ERBB2. In polarized epithelial cells, segregates ERBB2 and other ERBB receptors and prevents ERBB2 from acting as a coreceptor. The interaction with ERBB2 leads to enhanced expression of CDKN1B. The formation of a MUC4-ERBB2-ERBB3-NRG1 complex leads to down-regulation of CDKN1B, resulting in repression of apoptosis and stimulation of proliferation. Its ability to promote tumor growth may be mainly due to repression of apoptosis as opposed to proliferation

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.99

Clinical Summary— MUC4

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.99LOEUF

pLI 0.000

Z-score 1.61

OE 0.84 (0.70–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-18.87Z-score

OE missense 2.03 (1.96–2.00)

5424 obs / 2676.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.84 (0.70–0.99)

0≤0.351.4

Missense OE?2.03 (1.96–2.00)

0≤0.61.4

Synonymous OE?1.76

0≤1.21.6

LoF obs/exp: 93 / 111.3Missense obs/exp: 5424 / 2676.2Syn Z: -20.51

This gene — mechanism propensity

0.6260th %ile

GOF

0.3788th %ile

LOF

0.4528th %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.