IGFALS

Chr 16AR

insulin like growth factor binding protein acid labile subunit

Also known as: ACLSD, ALS

NCBI Gene: 3483 ENSG00000099769 UniProt: P35858 OMIM: 601489

The protein encoded by IGFALS is a serum protein containing leucine-rich repeats that binds insulin-like growth factors to increase their half-life and vascular localization, with production stimulated by growth hormone. Mutations cause acid-labile subunit deficiency, an autosomal recessive disorder manifesting as delayed and slow puberty. The gene shows low constraint to loss-of-function variation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a serum protein that binds insulin-like growth factors, increasing their half-life and their vascular localization. Production of the encoded protein, which contains twenty leucine-rich repeats, is stimulated by growth hormone. Defects in this gene are a cause of acid-labile subunit deficiency, which maifests itself in a delayed and slow puberty. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.841 OMIM phenotype

Clinical Summary— IGFALS

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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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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.84LOEUF

pLI 0.000

Z-score -0.84

OE 1.27 (0.83–1.84)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.22Z-score

OE missense 1.17 (1.08–1.26)

479 obs / 409.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.27 (0.83–1.84)

0≤0.351.4

Missense OE?1.17 (1.08–1.26)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 14 / 11.0Missense obs/exp: 479 / 409.5Syn Z: -2.15

This gene — mechanism propensity

0.6552th %ile

GOF

0.6930th %ile

LOF

0.3648th %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.