IGFALS

Chr 16AR

insulin like growth factor binding protein acid labile subunit

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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismARLOEUF 1.841 OMIM phenotype
Clinical SummaryIGFALS
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
Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
1.84LOEUF
pLI 0.000
Z-score -0.84
OE 1.27 (0.831.84)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-1.22Z-score
OE missense 1.17 (1.081.26)
479 obs / 409.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE1.27 (0.831.84)
00.351.4
Missense OE1.17 (1.081.26)
00.61.4
Synonymous OE1.19
01.21.6
LoF obs/exp: 14 / 11.0Missense obs/exp: 479 / 409.5Syn Z: -2.15
DN
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.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

IGFALS · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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