Is CRB1 p.Phe488Ser (c.1463T>C) pathogenic?

CRB1 p.Phe488Ser (c.1463T>C) is classified Conflicting classifications of pathogenicity in CRB1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-07). AlphaMissense: likely pathogenic (0.8742); Very rare (popmax 0.00267%, afr); Associated with Leber congenital amaurosis 8.

What condition is associated with CRB1 p.Phe488Ser (c.1463T>C)?

CRB1 p.Phe488Ser (c.1463T>C) is associated with Leber congenital amaurosis 8, retinitis pigmentosa 13, retinitis pigmentosa 12 (ClinVar).

How common is CRB1 p.Phe488Ser (c.1463T>C) in the general population?

CRB1 p.Phe488Ser (c.1463T>C) is very rare (popmax 0.00267%, afr) (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.Phe488Ser (c.1463T>C)?

AlphaMissense predicts likely pathogenic (score 0.8742) — an in-silico prediction, not a clinical call.

CRB1 p.Phe488Ser

c.1463T>C · rs777377174 · VCV978991

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leber congenital amaurosis 8

Computational evidence

Protein change
AlphaMissense	0.8742	likely pathogenic · top 5% in CRB1
REVEL	0.644	pathogenic-leaning
SaProt	LLR -11.74	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 4.5	GERP 0.54, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 209 kb · p 0.78 · regional, not allelic
Overall
CADD	22.4	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 0.00267% African / African-American · 2/74,932 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,182 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.Phe488Ser
Coding: c.1463T>C
MANE Select: NM_201253
dbSNP: rs777377174
Type: single nucleotide variant
Location: chr1:197421291 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 488: a UniProt-annotated variant site (in lca8); a UniProt-annotated variant site (in); 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: retinitis pigmentosa 13 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 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
CRB1 c.2843-1G>T 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-phe488ser (accessed [today's date]).

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