Is CLRN1 p.Leu46fs (c.121_136dup) pathogenic?

CLRN1 p.Leu46fs (c.121136dup) is classified Pathogenic/Likely pathogenic in CLRN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-05-03). Very rare (popmax 0.00446%, eas); Associated with CLRN1-related disorder.

What condition is associated with CLRN1 p.Leu46fs (c.121_136dup)?

CLRN1 p.Leu46fs (c.121_136dup) is associated with CLRN1-related disorder, retinitis pigmentosa 61, Usher syndrome type 3 (ClinVar).

How common is CLRN1 p.Leu46fs (c.121_136dup) in the general population?

CLRN1 p.Leu46fs (c.121_136dup) is very rare (popmax 0.00446%, eas) (gnomAD).

CLRN1 p.Leu46fs

c.121_136dup · rs767882032 · VCV651716

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

CLRN1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,890 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,894 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CLRN1
Protein: p.Leu46fs
Coding: c.121_136dup
MANE Select: NM_174878
dbSNP: rs767882032
Type: Duplication
Location: chr3:150972572 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.74

Full CLRN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CLRN1-related disorder

Also linked: retinitis pigmentosa 61 Usher syndrome type 3

Similar variants

CLRN1 p.Cys11fs Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.His67fs Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.Ile168fs Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.Val95fs Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.Gly68fs Likely pathogenic ★ same condition
CLRN1 p.Leu22fs Likely pathogenic ★ same condition
CLRN1 p.Thr37fs Likely pathogenic ★ same condition
CLRN1 p.Val198fs Likely pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/clrn1-p-leu46fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown