OBSL1

Chr 2AR

obscurin like cytoskeletal adaptor 1

ENSG00000124006 UniProt: O75147 OMIM: 610991

This gene encodes a cytoskeletal adaptor protein that functions as a core component of the 3M complex, which regulates microtubule dynamics and acts as a regulator of ubiquitin ligase pathways controlling Golgi morphogenesis and dendrite patterning in the brain. Biallelic mutations cause 3-M syndrome type 2, a growth disorder characterized by severe pre- and postnatal growth restriction with distinctive facial features, inherited in an autosomal recessive pattern. The gene shows very low constraint against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer (PubMed:24793695, PubMed:24793696). Acts as a regulator of the Cul7-RING(FBXW8) ubiquitin-protein ligase, playing a critical role in the ubiquitin ligase pathway that regulates Golgi morphogenesis and dendrite patterning in brain. Required to localize CUL7 to the Golgi apparatus in neurons

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

3-M syndrome 2MIM #612921

UniProt3M syndrome 2

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists 3-M syndrome 2; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.88

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.000

Z-score 2.42

OE 0.70 (0.55–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.01Z-score

OE missense 1.00 (0.95–1.05)

1170 obs / 1170.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.55–0.88)

0≤0.351.4

Missense OE?1.00 (0.95–1.05)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 51 / 73.4Missense obs/exp: 1170 / 1170.7Syn Z: -0.19

Background carrier burden — how many people carry a rare variant somewhere in OBSL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 15

2,910 rare PASS variants

Rare truncating (LoF)

1 in 220

456 rare PASS variants

Rare synonymous (reference)

1 in 25

1,299 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for OBSL1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 23	1 in 200
South Asian	~43k	1 in 12	1 in 160
Remaining (unassigned)	~30k	1 in 14	1 in 280
European (Finnish)	~27k	1 in 60	1 in 1,200
Admixed American	~22k	1 in 16	1 in 140
African / African American	~21k	1 in 16	1 in 170
East Asian	~20k	1 in 18	1 in 230
Ashkenazi Jewish	~13k	1 in 44	1 in 830
Middle Eastern	~2,884	1 in 13	1 in 360

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 20 of 21 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 20 of 21 (exon 21 below).? see exons ↓