Is CRB1 p.Arg365Pro (c.1094G>C) pathogenic?

CRB1 p.Arg365Pro (c.1094G>C) is classified Uncertain significance in CRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely benign (0.1461); Very rare (popmax 0.00237%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CRB1 p.Arg365Pro (c.1094G>C)?

CRB1 p.Arg365Pro (c.1094G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CRB1 p.Arg365Pro (c.1094G>C) in the general population?

CRB1 p.Arg365Pro (c.1094G>C) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about CRB1 p.Arg365Pro (c.1094G>C)?

AlphaMissense predicts likely benign (score 0.1461) — an in-silico prediction, not a clinical call.

CRB1 p.Arg365Pro

c.1094G>C · VCV4006686

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1461	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -12.22	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 -6.6	GERP -3.6
Regional constraint	o/e 1.01	unconstrained · MANE · 209 kb · p 0.78 · regional, not allelic
Overall
CADD	0.823	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 0.00237% European (non-Finnish) · 28/1,179,988 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,142
Admixed American	0.00167%	60,002

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.Arg365Pro
Coding: c.1094G>C
MANE Select: NM_201253
Type: single nucleotide variant
Location: chr1:197356936 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 365: the egf-like 9 domain; a UniProt-annotated variant site (in lca8); a disulfide bond

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRB1 p.Arg365His Conflicting classifications of pathogenicity ★ ⚠ same residue
CRB1 p.Arg365Ser Uncertain significance ★ ⚠ same residue
CRB1 p.Arg365Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CRB1 p.Arg365= Likely benign ★ same residue
CRB1 p.Ala921Val Uncertain significance ★★ ⚠ same condition
CRB1 p.Arg1286Trp Uncertain significance ★★ ⚠ same condition
CRB1 p.Arg1383Cys Uncertain significance ★★ ⚠ same condition
CRB1 p.Arg1383Leu Uncertain significance ★★ ⚠ 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-arg365pro (accessed [today's date]).

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