Is CRYBB3 p.Arg75Leu (c.224G>T) pathogenic?

CRYBB3 p.Arg75Leu (c.224G>T) is classified Uncertain significance in CRYBB3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-19). AlphaMissense: likely benign (0.1341); Rare (popmax 0.198%, mid); Associated with Inborn genetic diseases.

What condition is associated with CRYBB3 p.Arg75Leu (c.224G>T)?

CRYBB3 p.Arg75Leu (c.224G>T) is associated with Inborn genetic diseases, cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Arg75Leu (c.224G>T) in the general population?

CRYBB3 p.Arg75Leu (c.224G>T) is rare (popmax 0.198%, mid) (gnomAD).

What do computational predictors say about CRYBB3 p.Arg75Leu (c.224G>T)?

AlphaMissense predicts likely benign (score 0.1341) — an in-silico prediction, not a clinical call.

CRYBB3 p.Arg75Leu

c.224G>T · rs183587921 · VCV903286

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1341 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.198%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1341	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -10.16	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 1.9	GERP -0.81, phastCons 0.012
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	15.77	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 0.198% Middle Eastern · 12/6,062 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0895%

Overall 0.00719% 116/1,614,186 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.198%	505
Admixed American	0.0267%	3,752
Remaining individualsnot grpmax-eligible	0.024%	4,167
European (non-Finnish)	0.00576%	17,353
South Asian	0.00329%	30,361
African / African-American	0.00266%	37,524

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: CRYBB3
Protein: p.Arg75Leu
Coding: c.224G>T
MANE Select: NM_004076
dbSNP: rs183587921
Type: single nucleotide variant
Location: chr22:25203792 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 75: a UniProt-annotated variant site (in ctrct22; uncertain significance); the beta/gamma crystallin 'greek key' 2 domain

Full CRYBB3 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

Also linked: cataract 22 multiple types

Similar variants

CRYBB3 p.Arg75Cys Uncertain significance ★★ ⚠ same residue
CRYBB3 p.Arg75His Uncertain significance ★★ ⚠ same residue
CRYBB3 p.Arg127Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg127His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg152Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg169Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg179His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg196His 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/crybb3-p-arg75leu (accessed [today's date]).

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