CLRN1

Chr 3AR

clarin 1

Also known as: RP61, USH3, USH3A

NCBI Gene: 7401 ENSG00000163646 UniProt: P58418 OMIM: 606397

This gene encodes a transmembrane protein with an endoplasmic reticulum retention signal that functions at excitatory ribbon synapses between hair cells and cochlear ganglion cells, and likely at analogous retinal synapses. Mutations cause Usher syndrome type IIIa, which affects both hearing and vision with progressive hearing loss typically beginning in childhood or adolescence. The gene shows autosomal recessive inheritance and is highly intolerant to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that contains a cytosolic N-terminus, multiple helical transmembrane domains, and an endoplasmic reticulum membrane retention signal, TKGH, in the C-terminus. The encoded protein may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIIa. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Retinitis pigmentosa 61MIM #614180

Usher syndrome, type 3AMIM #276902

UniProtUsher syndrome 3A

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Usher syndrome type 3 · AR · ClinGen 2017

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

1.80

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — CLRN1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.80LOEUF

pLI 0.000

Z-score -0.49

OE 1.17 (0.73–1.80)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.59Z-score

OE missense 1.15 (1.00–1.31)

150 obs / 130.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.17 (0.73–1.80)

0≤0.351.4

Missense OE?1.15 (1.00–1.31)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 11 / 9.4Missense obs/exp: 150 / 130.9Syn Z: 0.24

Background carrier burden — how many people carry a rare variant somewhere in CLRN1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

442 rare PASS variants

Rare truncating (LoF)

1 in 330

64 rare PASS variants

Rare synonymous (reference)

1 in 320

133 rare PASS variants

Rare missense and truncating variants are carried at similar rates in CLRN1; this gene does not show strong loss-of-function constraint by this measure. 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 180	1 in 1,200
South Asian	~43k	1 in 170	1 in 420
Remaining (unassigned)	~30k	1 in 120	1 in 450
European (Finnish)	~27k	1 in 320	1 in 5,200
Admixed American	~22k	1 in 130	1 in 1,000
African / African American	~21k	1 in 110	1 in 460
East Asian	~20k	1 in 130	1 in 3,300
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 220	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓