Is CRB2 p.Pro949Arg (c.2846C>G) pathogenic?

CRB2 p.Pro949Arg (c.2846C>G) is classified Uncertain significance in CRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely benign (0.2278); Ultra-rare (popmax 0.0244%, mid).

How common is CRB2 p.Pro949Arg (c.2846C>G) in the general population?

CRB2 p.Pro949Arg (c.2846C>G) is ultra-rare (popmax 0.0244%, mid) (gnomAD).

What do computational predictors say about CRB2 p.Pro949Arg (c.2846C>G)?

AlphaMissense predicts likely benign (score 0.2278) — an in-silico prediction, not a clinical call.

CRB2 p.Pro949Arg

c.2846C>G · rs1190791808 · VCV1035411

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2278 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0244%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2278	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP 0.31, phastCons 0.86
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.85 · regional, not allelic
Overall
CADD	17.29	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0244% Middle Eastern · 1/4,090 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00152%

Overall 0.0023% 33/1,431,766 alleles · ultra-rare exomes 33/1,279,934 · genomes 0/151,832 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0244%	4,090
Remaining individualsnot grpmax-eligible	0.00549%	18,225
European (non-Finnish)	0.00255%	39,263
South Asian	0.00138%	72,292

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.Pro949Arg
Coding: c.2846C>G
MANE Select: NM_173689
dbSNP: rs1190791808
Type: single nucleotide variant
Location: chr9:123373377 (GRCh38)
Gene constraint: LOEUF 1.202 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.95 · 1 PDB
Residue 949: a UniProt-annotated variant site (in vmckd; uncertain significance); the laminin g-like 3 domain; a UniProt-annotated variant site (in fsgs9; uncertain significance)

Full CRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRB2 p.Pro949= Likely benign ★ same residue
CRB2 p.Arg275Ter Pathogenic ★★ same type
CRB2 p.Cys105Ter Pathogenic/Likely pathogenic ★★ same type
CRB2 p.Gly1205Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
CRB2 p.Trp759Ter Pathogenic ★★ same type
CRB2 p.Ala1042Thr Uncertain significance ★★ ⚠ same type
CRB2 p.Ala1266Pro Uncertain significance ★★ ⚠ same type
CRB2 p.Ala228Thr Uncertain significance ★★ ⚠ same type

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-pro949arg (accessed [today's date]).

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