Is CLRN1 p.Ile168fs (c.502dup) pathogenic?

CLRN1 p.Ile168fs (c.502dup) is classified Pathogenic/Likely pathogenic in CLRN1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-24). Very rare (popmax 0.00167%, amr); Associated with CLRN1-related disorder.

What condition is associated with CLRN1 p.Ile168fs (c.502dup)?

CLRN1 p.Ile168fs (c.502dup) is associated with CLRN1-related disorder, Usher syndrome type 3A, retinitis pigmentosa 61 (ClinVar).

How common is CLRN1 p.Ile168fs (c.502dup) in the general population?

CLRN1 p.Ile168fs (c.502dup) is very rare (popmax 0.00167%, amr) (gnomAD).

CLRN1 p.Ile168fs

c.502dup · rs746523071 · VCV188875

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,810 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,613,204 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,810
Remaining individualsnot grpmax-eligible	0.0016%	62,446
African / African-American	0.00134%	74,750
European (non-Finnish)	0.000763%	131,097

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.Ile168fs
Coding: c.502dup
MANE Select: NM_174878
dbSNP: rs746523071
Type: Duplication
Location: chr3:150928132 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.74
Residue 168: a UniProt-annotated variant site (in ush3a)

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

Disease context

CLRN1-related disorder

Also linked: Usher syndrome type 3A retinitis pigmentosa 61 Usher syndrome type 3 inherited retinal dystrophy Usher syndrome

Similar variants

CLRN1 p.Ile168Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
CLRN1 p.Cys11fs Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.His67fs Pathogenic/Likely pathogenic ★★ same condition
CLRN1 p.Leu46fs 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

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-ile168fs (accessed [today's date]).

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