ACVR1B

Chr 12

activin A receptor type 1B

Also known as: ACTRIB, ACVRLK4, ALK4, SKR2

NCBI Gene: 91 ENSG00000135503 UniProt: P36896 OMIM: 601300

This gene encodes a transmembrane serine/threonine kinase that functions as an activin type I receptor, transducing activin signals through SMAD-mediated pathways to regulate neuronal differentiation and survival, along with multiple other developmental processes. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.17), but currently has only somatic cancer associations in OMIM rather than established germline developmental disorders. Activin signaling is critical for nervous system development, suggesting potential for neurodevelopmental phenotypes from germline mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an activin A type IB receptor. Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I and two type II receptors. This protein is a type I receptor which is essential for signaling. Mutations in this gene are associated with pituitary tumors. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jun 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.171 OMIM phenotype

Clinical Summary— ACVR1B

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 38 VUS of 51 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.17LOEUF

pLI 1.000

Z-score 4.69

OE 0.04 (0.01–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.37Z-score

OE missense 0.47 (0.41–0.54)

148 obs / 317.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.17)

0≤0.351.4

Missense OE?0.47 (0.41–0.54)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 1 / 27.5Missense obs/exp: 148 / 317.0Syn Z: 0.55

This gene — mechanism propensity

0.3694th %ile

GOF

0.5857th %ile

LOF

0.70top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.17

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

51 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS38

Benign2

Pathogenic

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	0	0	3
Likely Pathogenic	0	0	0	0	0
VUS	0	38	0	0	38
Likely Benign	0	0	0	0	0
Benign	0	0	1	1	2
Total	2	39	1	1	43

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap ACVR1B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →