Is CRYBB3 p.Pro164= (c.492C>A) pathogenic?

CRYBB3 p.Pro164= (c.492C>A) is classified Likely benign in CRYBB3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-08). Rare (popmax 0.188%, afr); Associated with cataract 22 multiple types.

What condition is associated with CRYBB3 p.Pro164= (c.492C>A)?

CRYBB3 p.Pro164= (c.492C>A) is associated with cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Pro164= (c.492C>A) in the general population?

CRYBB3 p.Pro164= (c.492C>A) is rare (popmax 0.188%, 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.

CRYBB3 p.Pro164=

c.492C>A · rs139487214 · VCV466360

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.188%, afr)

Conditions

cataract 22 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.4
Overall
CADD	0.054	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.188% African / African-American · 141/75,048 alleles

Filtering AF 0.163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.153%

Overall 0.00992% 160/1,613,452 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.188%	532
Admixed American	0.0167%	6,003
Remaining individualsnot grpmax-eligible	0.0128%	7,811
European (non-Finnish)	8.48e-05%	1,179,528

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.Pro164=
Coding: c.492C>A
MANE Select: NM_004076
dbSNP: rs139487214
Type: single nucleotide variant
Location: chr22:25207068 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 164: a turn; 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-pro164 (accessed [today's date]).

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