Is CRB1 p.Ser1046Phe (c.3137C>T) pathogenic?

CRB1 p.Ser1046Phe (c.3137C>T) is classified Uncertain significance in CRB1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-08). AlphaMissense: likely benign (0.1515); Absent from gnomAD v4.1; Associated with Leber congenital amaurosis 8.

What condition is associated with CRB1 p.Ser1046Phe (c.3137C>T)?

CRB1 p.Ser1046Phe (c.3137C>T) is associated with Leber congenital amaurosis 8, pigmented paravenous retinochoroidal atrophy, retinitis pigmentosa 12 (ClinVar).

How common is CRB1 p.Ser1046Phe (c.3137C>T) in the general population?

CRB1 p.Ser1046Phe (c.3137C>T) is absent from gnomAD v4.1 (gnomAD).

How is Leber congenital amaurosis inherited?

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

What do computational predictors say about CRB1 p.Ser1046Phe (c.3137C>T)?

AlphaMissense predicts likely benign (score 0.1515) — an in-silico prediction, not a clinical call.

CRB1 p.Ser1046Phe

c.3137C>T · rs1665065652 · VCV1384341

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1515 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Leber congenital amaurosis 8

Computational evidence

Protein change
AlphaMissense	0.1515	likely benign
REVEL	0.368	indeterminate
SaProt	LLR -10.28	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 0.92, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 209 kb · p 0.78 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CRB1
Protein: p.Ser1046Phe
Coding: c.3137C>T
MANE Select: NM_201253
dbSNP: rs1665065652
Type: single nucleotide variant
Location: chr1:197435000 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 1046: a UniProt-annotated variant site (in lca8); the laminin g-like 3 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.Ser1046Pro 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
CRB1 c.2842+5G>A 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-ser1046phe (accessed [today's date]).

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