Is CRB1 p.Ser487Pro (c.1459T>C) pathogenic?

CRB1 p.Ser487Pro (c.1459T>C) is classified Pathogenic/Likely pathogenic in CRB1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-13). AlphaMissense: likely pathogenic (0.8442); Very rare (popmax 0.0022%, sas); Associated with CRB1-related disorder.

What condition is associated with CRB1 p.Ser487Pro (c.1459T>C)?

CRB1 p.Ser487Pro (c.1459T>C) is associated with CRB1-related disorder, retinitis pigmentosa 12, Leber congenital amaurosis (ClinVar).

How common is CRB1 p.Ser487Pro (c.1459T>C) in the general population?

CRB1 p.Ser487Pro (c.1459T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CRB1 p.Ser487Pro (c.1459T>C)?

AlphaMissense predicts likely pathogenic (score 0.8442) — an in-silico prediction, not a clinical call.

CRB1 p.Ser487Pro

c.1459T>C · rs1664298414 · VCV2572562

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8442 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CRB1-related disorder

Computational evidence

Protein change
AlphaMissense	0.8442	likely pathogenic ✓ concordant with ClinVar · top 6% in CRB1
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -15.13	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 2	GERP -0.83, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 209 kb · p 0.78 · regional, not allelic
Overall
CADD	21.6	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

Grpmax group 0.0022% South Asian · 2/91,082 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,892 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.Ser487Pro
Coding: c.1459T>C
MANE Select: NM_201253
dbSNP: rs1664298414
Type: single nucleotide variant
Location: chr1:197421287 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 487: 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

CRB1-related disorder

Also linked: retinitis pigmentosa 12 Leber congenital amaurosis inherited retinal dystrophy

Similar variants

CRB1 p.Ser487Ala 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.2676+1G>T 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-ser487pro (accessed [today's date]).

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