Is CRB1 p.Cys412Phe (c.1235G>T) pathogenic?

CRB1 p.Cys412Phe (c.1235G>T) is classified Uncertain significance in CRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). AlphaMissense: likely pathogenic (0.8809); Absent from gnomAD v4.1; Associated with retinitis pigmentosa 12.

What condition is associated with CRB1 p.Cys412Phe (c.1235G>T)?

CRB1 p.Cys412Phe (c.1235G>T) is associated with retinitis pigmentosa 12 (ClinVar).

How common is CRB1 p.Cys412Phe (c.1235G>T) in the general population?

CRB1 p.Cys412Phe (c.1235G>T) is absent from gnomAD v4.1 (gnomAD).

How is Retinitis pigmentosa 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.Cys412Phe (c.1235G>T)?

AlphaMissense predicts likely pathogenic (score 0.8809) — an in-silico prediction, not a clinical call.

CRB1 p.Cys412Phe

c.1235G>T · rs2125468972 · VCV1333629

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8809 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa 12

Computational evidence

Protein change
AlphaMissense	0.8809	likely pathogenic · top 5% in CRB1
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -12.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 209 kb · p 0.78 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Cys412Phe
Coding: c.1235G>T
MANE Select: NM_201253
dbSNP: rs2125468972
Type: single nucleotide variant
Location: chr1:197421063 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 412: a UniProt-annotated variant site (in lca8); the egf-like 10; calcium-binding 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

For Retinitis pigmentosa (Orphanet):

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

Similar variants

CRB1 p.Cys412Ter Pathogenic ★ same residue
CRB1 p.Cys412= Likely benign ★ same residue
CRB1 p.Cys412Tyr 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

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-cys412phe (accessed [today's date]).

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