GUCA2B

Chr 1

guanylate cyclase activator 2B

ENSG00000044012 UniProt: Q16661 OMIM: 601271

The protein encoded by this gene is processed to generate uroguanylin, an endogenous activator of intestinal guanylate cyclase that regulates fluid and electrolyte transport in the intestine and kidneys by stimulating cyclic GMP production. Mutations in GUCA2B cause autosomal recessive meconium ileus, a neonatal intestinal obstruction disorder affecting newborns. The gene shows moderate tolerance to loss-of-function variants with relatively high constraint metrics.

OMIM ResearchSummary from RefSeq, UniProt

Endogenous activator of intestinal guanylate cyclase. It stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins. May be a potent physiological regulator of intestinal fluid and electrolyte transport. May be an autocrine/paracrine regulator of intestinal salt and water transport

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.98

Clinical Summary— GUCA2B

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.21) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.381

Z-score 1.62

OE 0.21 (0.07–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.32Z-score

OE missense 0.89 (0.72–1.10)

61 obs / 68.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.07–0.98)

0≤0.351.4

Missense OE?0.89 (0.72–1.10)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 1 / 4.8Missense obs/exp: 61 / 68.5Syn Z: -0.76

This gene — mechanism propensity

0.5082th %ile

GOF

0.6640th %ile

LOF

0.3356th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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.