Is CRB3 p.Pro15Arg (c.44C>G) pathogenic?

CRB3 p.Pro15Arg (c.44C>G) is classified Uncertain significance in CRB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely benign (0.2543); Ultra-rare (popmax 0.0215%, mid).

How common is CRB3 p.Pro15Arg (c.44C>G) in the general population?

CRB3 p.Pro15Arg (c.44C>G) is ultra-rare (popmax 0.0215%, mid) (gnomAD).

What do computational predictors say about CRB3 p.Pro15Arg (c.44C>G)?

AlphaMissense predicts likely benign (score 0.2543) — an in-silico prediction, not a clinical call.

CRB3 p.Pro15Arg

c.44C>G · VCV3496924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2543 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0215%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2543	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -11.64	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.26, phastCons 0.051
Regional constraint	o/e 0.96	unconstrained · MANE · 1,967 bp · p 0.62 · regional, not allelic
Overall
CADD	17.55	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 0.0215% Middle Eastern · 1/4,660 alleles

Filtering AF 0.00294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00151%

Overall 0.00237% 30/1,265,320 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0215%	4,660
South Asian	0.0111%	9,015
Remaining individualsnot grpmax-eligible	0.00425%	23,521
African / African-American	0.00303%	32,975
East Asian	0.00293%	34,176
Finnishnot grpmax-eligible	0.00279%	35,896
European (non-Finnish)	0.00199%	50,201

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: CRB3
Protein: p.Pro15Arg
Coding: c.44C>G
MANE Select: NM_139161
Type: single nucleotide variant
Location: chr19:6464745 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 69.83 · 1 PDB

Full CRB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRB3 c.*294G>A Uncertain significance ★ same type
CRB3 c.*300C>T Uncertain significance ★ same type
CRB3 c.*304C>T Uncertain significance ★ same type
CRB3 c.*314C>G Uncertain significance ★ same type
CRB3 c.*342C>T Uncertain significance ★ same type
CRB3 p.Ala11Glu Uncertain significance ★ same type
CRB3 p.Arg20Cys Uncertain significance ★ ⚠ same type
CRB3 p.Arg94Trp 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/crb3-p-pro15arg (accessed [today's date]).

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