Is CRB1 p.Ala1374= (c.4122A>T) pathogenic?

CRB1 p.Ala1374= (c.4122A>T) is classified Likely benign in CRB1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-04-28). Very rare (popmax 0.00134%, afr); Associated with Leber congenital amaurosis 8.

What condition is associated with CRB1 p.Ala1374= (c.4122A>T)?

CRB1 p.Ala1374= (c.4122A>T) is associated with Leber congenital amaurosis 8, retinitis pigmentosa 12, Leber congenital amaurosis (ClinVar).

How common is CRB1 p.Ala1374= (c.4122A>T) in the general population?

CRB1 p.Ala1374= (c.4122A>T) is very rare (popmax 0.00134%, afr) (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.Ala1374=

c.4122A>T · rs1667263346 · VCV1674637

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Leber congenital amaurosis 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -3.7
Overall
CADD	1.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,880 alleles

Overall 0.000657% 1/152,098 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.Ala1374=
Coding: c.4122A>T
MANE Select: NM_201253
dbSNP: rs1667263346
Type: single nucleotide variant
Location: chr1:197477780 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 1374: a UniProt-annotated variant site (in lca8); the 'interaction with epb41l5' region

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: retinitis pigmentosa 12 Leber congenital amaurosis

For Leber congenital amaurosis (Orphanet):

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

Similar variants

CRB1 p.Ala1374fs Pathogenic ★★ same residue
CRB1 p.Ala1374Val Uncertain significance ★ ⚠ same residue
CRB1 c.1172-2A>G Likely pathogenic ★★ same condition
CRB1 c.2128+1G>C Pathogenic/Likely pathogenic ★★ same condition
CRB1 c.2129-1G>A Pathogenic/Likely pathogenic ★★ same condition
CRB1 c.2129-1G>C Pathogenic ★★ same condition
CRB1 c.2129-2A>G Pathogenic ★★ same condition
CRB1 c.2676+1G>A 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-ala1374 (accessed [today's date]).

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