Is CRYBB2 p.Arg145Trp (c.433C>T) pathogenic?

CRYBB2 p.Arg145Trp (c.433C>T) is classified Uncertain significance in CRYBB2 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-03). AlphaMissense: ambiguous (0.4591); Very rare (popmax 0.00534%, afr); Associated with cataract 3 multiple types.

What condition is associated with CRYBB2 p.Arg145Trp (c.433C>T)?

CRYBB2 p.Arg145Trp (c.433C>T) is associated with cataract 3 multiple types (ClinVar).

How common is CRYBB2 p.Arg145Trp (c.433C>T) in the general population?

CRYBB2 p.Arg145Trp (c.433C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CRYBB2 p.Arg145Trp (c.433C>T)?

AlphaMissense predicts ambiguous (score 0.4591) — an in-silico prediction, not a clinical call.

CRYBB2 p.Arg145Trp

c.433C>T · rs2330991 · VCV2628849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

cataract 3 multiple types

Computational evidence

Protein change
AlphaMissense	0.4591	ambiguous
REVEL	0.751	pathogenic-leaning
SaProt	LLR -9.59	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -3.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	26.8	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 0.00534% African / African-American · 4/74,952 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00155% 25/1,614,124 alleles · very rare exomes 20/1,461,864 · genomes 5/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,738
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Admixed American	0.00333%	30,007
Remaining individualsnot grpmax-eligible	0.0032%	31,245
East Asian	0.00223%	44,894
European (non-Finnish)	0.00127%	78,670

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: CRYBB2
Protein: p.Arg145Trp
Coding: c.433C>T
MANE Select: NM_000496
dbSNP: rs2330991
Type: single nucleotide variant
Location: chr22:25229562 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 145: a β-strand; the beta/gamma crystallin 'greek key' 3 domain

Full CRYBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 3 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYBB2 p.Arg145Pro Uncertain significance ★ ⚠ same residue
CRYBB2 p.Arg188Cys Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 p.Arg188His Pathogenic ★★ same condition
CRYBB2 p.Gln155Ter Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 p.Gly119Arg Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 p.Arg160Pro Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Gly57Glu Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Gly61Ser 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/crybb2-p-arg145trp (accessed [today's date]).

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