Is CRYBB3 p.Arg75Cys (c.223C>T) pathogenic?

CRYBB3 p.Arg75Cys (c.223C>T) is classified Uncertain significance in CRYBB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-14). AlphaMissense: likely benign (0.0942); Ultra-rare (popmax 0.0307%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRYBB3 p.Arg75Cys (c.223C>T)?

CRYBB3 p.Arg75Cys (c.223C>T) is associated with Inborn genetic diseases, cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Arg75Cys (c.223C>T) in the general population?

CRYBB3 p.Arg75Cys (c.223C>T) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

What do computational predictors say about CRYBB3 p.Arg75Cys (c.223C>T)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

CRYBB3 p.Arg75Cys

c.223C>T · VCV3683144

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP 0.37
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	16.8	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 0.0307% African / African-American · 23/74,930 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00198% 32/1,614,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,258
Remaining individualsnot grpmax-eligible	0.008%	12,497
East Asian	0.00223%	44,888
South Asian	0.0022%	45,544
European (non-Finnish)	8.47e-05%	1,180,032

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.Arg75Cys
Coding: c.223C>T
MANE Select: NM_004076
Type: single nucleotide variant
Location: chr22:25203791 (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.Arg75His Uncertain significance ★★ ⚠ same residue
CRYBB3 p.Arg75Leu 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-arg75cys (accessed [today's date]).

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