IGFALS

Chr 16AR

insulin like growth factor binding protein acid labile subunit

Also known as: ACLSD, ALS

NCBI Gene: 3483ENSG00000099769UniProt: P35858

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]

Primary Disease Associations & Inheritance

Acid-labile subunit, deficiency ofMIM #615961
AR
355
ClinVar variants
50
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— IGFALS
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
50 Pathogenic / Likely Pathogenic· 238 VUS of 355 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-1.22Z-score
OE missense 1.17 (1.08–1.26)
479 obs / 409.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.27 (0.83–1.84)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.17 (1.08–1.26)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.19
0≤1.21.6
LoF obs/exp: 14 / 11.0Missense obs/exp: 479 / 409.5Syn Z: -2.15

ClinVar Variant Classifications

355 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41
Likely Pathogenic9
VUS238
Likely Benign38
Benign17
Conflicting12
41
Pathogenic
9
Likely Pathogenic
238
VUS
38
Likely Benign
17
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
38
0
41
Likely Pathogenic
5
2
2
0
9
VUS
2
195
30
11
238
Likely Benign
0
14
3
21
38
Benign
1
4
2
10
17
Conflicting
—12
Total102167542355

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

View 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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Acid-labile subunit, deficiency of

MIM #615961

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
IGFALS suppresses hepatocellular carcinoma progression by stabilizing PPAR-γ.
Xu L et al.·Int Immunopharmacol
2024
Genetic disorders of GH action pathway.
Domené HM et al.·Growth Horm IGF Res
2018Review
Pathogenic/likely pathogenic variants in the SHOX, GHR and IGFALS genes among Indian children with idiopathic short stature.
Kumar A et al.·J Pediatr Endocrinol Metab
2020
The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature.
Toni L et al.·Horm Res Paediatr
2024
Atypical defects resulting in growth hormone insensitivity.
Wit JM et al.·Growth Horm IGF Res
2016Review
Novel potential biomarkers for severe alcoholic liver disease.
Huang J et al.·Front Immunol
2022
Genetic evaluation of short stature.
Wit JM et al.·Best Pract Res Clin Endocrinol Metab
2011Review
Genetic causes of growth hormone insensitivity beyond GHR.
Hwa V et al.·Rev Endocr Metab Disord
2021Review
A pure de novo 16p13.3 duplication and amplification in a patient with femoral hypoplasia, psychomotor retardation, heart defect, and facial dysmorphism-a case report and literature review of the partial 16p13.3 trisomy syndrome.
Socha M et al.·J Appl Genet
2023Review
Spectrum of insulin-like growth factor deficiency.
Wit JM et al.·Endocr Dev
2012Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Klinefelter Syndrome

Klinefelter Syndrome and Testosterone Treatment in Puberty

RECRUITING
NCT06294990Phase PHASE4Lise AksglædeStarted 2024-08-15
Testosterone gelPlacebo

External Resources

Links to major genomics databases and tools