Is CRYBB3 p.Val159Ile (c.475G>A) pathogenic?

CRYBB3 p.Val159Ile (c.475G>A) is classified Benign/Likely benign in CRYBB3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.2194); Low-frequency (popmax 2.89%, afr); Associated with cataract 22 multiple types.

What condition is associated with CRYBB3 p.Val159Ile (c.475G>A)?

CRYBB3 p.Val159Ile (c.475G>A) is associated with cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Val159Ile (c.475G>A) in the general population?

CRYBB3 p.Val159Ile (c.475G>A) is low-frequency (popmax 2.89%, afr) (gnomAD).

How is Early onset non-syndromic cataract inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CRYBB3 p.Val159Ile (c.475G>A)?

AlphaMissense predicts likely benign (score 0.2194) — an in-silico prediction, not a clinical call.

CRYBB3 p.Val159Ile

c.475G>A · rs4455261 · VCV466359

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2194 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.89%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cataract 22 multiple types

Computational evidence

Protein change
AlphaMissense	0.2194	likely benign
REVEL	0.44	indeterminate
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	25.8	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 2.89% African / African-American · 2,172/75,032 alleles

Filtering AF 2.79% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.75%

Overall 0.169% 2,723/1,613,160 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.89%	35
Admixed American	0.468%	214
Remaining individualsnot grpmax-eligible	0.264%	379
Middle Eastern	0.0825%	1,212
South Asian	0.00879%	11,382
European (non-Finnish)	0.0078%	12,819

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.Val159Ile
Coding: c.475G>A
MANE Select: NM_004076
dbSNP: rs4455261
Type: single nucleotide variant
Location: chr22:25207051 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 159: a UniProt-annotated variant site (in); a β-strand; the beta/gamma crystallin 'greek key' 4 domain

Full CRYBB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 22 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

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.Arg207His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg75Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg75His 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-val159ile (accessed [today's date]).

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