Is CRB1 p.Val554fs (c.1660del) pathogenic?

CRB1 p.Val554fs (c.1660del) is classified Pathogenic in CRB1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-23). Very rare (popmax 0.000169%, nfe); Associated with Leber congenital amaurosis 8.

What condition is associated with CRB1 p.Val554fs (c.1660del)?

CRB1 p.Val554fs (c.1660del) is associated with Leber congenital amaurosis 8, pigmented paravenous retinochoroidal atrophy, retinitis pigmentosa 12 (ClinVar).

How common is CRB1 p.Val554fs (c.1660del) in the general population?

CRB1 p.Val554fs (c.1660del) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Leber congenital amaurosis inherited?

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

CRB1 p.Val554fs

c.1660del · rs1664313783 · VCV1384992

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Leber congenital amaurosis 8

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 0.37	GERP -3.5

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,038 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,886 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.Val554fs
Coding: c.1660del
MANE Select: NM_201253
dbSNP: rs1664313783
Type: Deletion
Location: chr1:197421487 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 554: a UniProt-annotated variant site (in lca8); the laminin g-like 1 domain

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

Disease context

Leber congenital amaurosis 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pigmented paravenous retinochoroidal atrophy retinitis pigmentosa 12

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CRB1 p.Val554Gly Uncertain significance ★★ ⚠ same residue
CRB1 p.Val554Leu Uncertain significance ★ ⚠ same residue
CRB1 c.652+3_652+6del Pathogenic/Likely pathogenic ★★ same condition
CRB1 p.Ala1374fs Pathogenic ★★ same condition
CRB1 p.Asn7fs Pathogenic/Likely pathogenic ★★ same condition
CRB1 p.Asp1299fs Pathogenic/Likely pathogenic ★★ same condition
CRB1 p.Asp47fs Pathogenic ★★ same condition
CRB1 p.Cys1143fs Pathogenic/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/crb1-p-val554fs (accessed [today's date]).

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