Is CRB1 p.His447fs (c.1339dup) pathogenic?

CRB1 p.His447fs (c.1339dup) is classified Pathogenic in CRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). Very rare (popmax 8.47e-05%, nfe); Associated with retinitis pigmentosa 12.

What condition is associated with CRB1 p.His447fs (c.1339dup)?

CRB1 p.His447fs (c.1339dup) is associated with retinitis pigmentosa 12, Leber congenital amaurosis 8 (ClinVar).

How common is CRB1 p.His447fs (c.1339dup) in the general population?

CRB1 p.His447fs (c.1339dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CRB1 p.His447fs

c.1339dup · rs2125469313 · VCV1426442

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

retinitis pigmentosa 12

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 6 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.83	GERP -3.7

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.84e-05% 1/1,461,872 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: CRB1
Protein: p.His447fs
Coding: c.1339dup
MANE Select: NM_201253
dbSNP: rs2125469313
Type: Duplication
Location: chr1:197421164 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 447: a UniProt-annotated variant site (in lca8); the egf-like 11 domain; a disulfide bond

Full CRB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leber congenital amaurosis 8

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CRB1 c.3878+2dup Likely pathogenic ★★ same condition
CRB1 p.Cys1240fs Pathogenic ★★ same condition
CRB1 p.Ile20fs Pathogenic/Likely pathogenic ★★ same condition
CRB1 p.Ile211fs Pathogenic/Likely pathogenic ★★ same condition
CRB1 p.Ile384fs Pathogenic/Likely pathogenic ★★ same condition
CRB1 p.Ser345fs Pathogenic/Likely pathogenic ★★ same condition
CRB1 p.Ser586fs Pathogenic/Likely pathogenic ★★ same condition
CRB1 p.Leu613_Gly614insVal Uncertain significance ★★ 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/crb1-p-his447fs (accessed [today's date]).

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