Is CRB2 p.Arg279Pro (c.836G>C) pathogenic?

CRB2 p.Arg279Pro (c.836G>C) is classified Likely benign in CRB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). AlphaMissense: likely pathogenic (0.8463); Rare (popmax 0.165%, sas); Associated with Inborn genetic diseases.

What condition is associated with CRB2 p.Arg279Pro (c.836G>C)?

CRB2 p.Arg279Pro (c.836G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CRB2 p.Arg279Pro (c.836G>C) in the general population?

CRB2 p.Arg279Pro (c.836G>C) is rare (popmax 0.165%, sas) (gnomAD).

What do computational predictors say about CRB2 p.Arg279Pro (c.836G>C)?

AlphaMissense predicts likely pathogenic (score 0.8463) — an in-silico prediction, not a clinical call.

CRB2 p.Arg279Pro

c.836G>C · rs536555517 · VCV1963759

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8463 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8463	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -9.24	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.43, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.85 · regional, not allelic
Overall
CADD	28.6	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 0.165% South Asian · 148/89,782 alleles

Filtering AF 0.143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.135%

Overall 0.0101% 161/1,596,802 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.165%	607
Remaining individualsnot grpmax-eligible	0.0194%	5,167
African / African-American	0.00135%	74,238

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: CRB2
Protein: p.Arg279Pro
Coding: c.836G>C
MANE Select: NM_173689
dbSNP: rs536555517
Type: single nucleotide variant
Location: chr9:123367253 (GRCh38)
Gene constraint: LOEUF 1.202 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.95 · 1 PDB
Residue 279: the 'required for maximum inhibition of app amyloid-beta peptide secretion' region; a disulfide bond; the egf-like 6 domain; a UniProt-annotated variant site (in fsgs9; uncertain significance)

Full CRB2 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

CRB2 p.Arg279Leu Uncertain significance ★ ⚠ same residue
CRB2 p.Ala1042Thr Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala1266Pro Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala228Thr Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala26Asp Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala325Val Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala80Thr Uncertain significance ★★ ⚠ same condition
CRB2 p.Ala887Thr 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/crb2-p-arg279pro (accessed [today's date]).

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