Is CRB1 p.Phe742Ser (c.2225T>C) pathogenic?

CRB1 p.Phe742Ser (c.2225T>C) is classified Conflicting classifications of pathogenicity in CRB1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-29). AlphaMissense: ambiguous (0.4725); Ultra-rare (popmax 0.0467%, afr); Associated with retinitis pigmentosa.

What condition is associated with CRB1 p.Phe742Ser (c.2225T>C)?

CRB1 p.Phe742Ser (c.2225T>C) is associated with retinitis pigmentosa, retinitis pigmentosa 12, Leber congenital amaurosis 8 (ClinVar).

How common is CRB1 p.Phe742Ser (c.2225T>C) in the general population?

CRB1 p.Phe742Ser (c.2225T>C) is ultra-rare (popmax 0.0467%, afr) (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.Phe742Ser (c.2225T>C)?

AlphaMissense predicts ambiguous (score 0.4725) — an in-silico prediction, not a clinical call.

CRB1 p.Phe742Ser

c.2225T>C · rs140494140 · VCV294675

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4725 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.4725	ambiguous
REVEL	0.664	pathogenic-leaning
SaProt	LLR -4.39	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 209 kb · p 0.78 · regional, not allelic
Overall
CADD	23.9	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 0.0467% African / African-American · 35/74,906 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0303%

Overall 0.00242% 39/1,613,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0467%	2,140
Admixed American	0.005%	19,985
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Phe742Ser
Coding: c.2225T>C
MANE Select: NM_201253
dbSNP: rs140494140
Type: single nucleotide variant
Location: chr1:197427550 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 742: a UniProt-annotated variant site (in lca8); the laminin g-like 2 domain

Full CRB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 12 Leber congenital amaurosis 8 Leber congenital amaurosis

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.Phe742= Likely benign ★ 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-phe742ser (accessed [today's date]).

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