Is CRYBB2 p.Pro58Leu (c.173C>T) pathogenic?

CRYBB2 p.Pro58Leu (c.173C>T) is classified Likely pathogenic in CRYBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-22). AlphaMissense: likely pathogenic (0.8088); Very rare (popmax 0.00136%, afr); Associated with cataract 3 multiple types.

What condition is associated with CRYBB2 p.Pro58Leu (c.173C>T)?

CRYBB2 p.Pro58Leu (c.173C>T) is associated with cataract 3 multiple types (ClinVar).

How common is CRYBB2 p.Pro58Leu (c.173C>T) in the general population?

CRYBB2 p.Pro58Leu (c.173C>T) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about CRYBB2 p.Pro58Leu (c.173C>T)?

AlphaMissense predicts likely pathogenic (score 0.8088) — an in-silico prediction, not a clinical call.

CRYBB2 p.Pro58Leu

c.173C>T · rs763268420 · VCV1210343

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8088 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cataract 3 multiple types

Computational evidence

Protein change
AlphaMissense	0.8088	likely pathogenic ✓ concordant with ClinVar
REVEL	0.462	indeterminate
SaProt	LLR -11.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	32.0	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 0.00136% African / African-American · 1/73,760 alleles

Filtering AF 0.00013% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.5e-05%

Overall 0.000515% 8/1,552,392 alleles · very rare exomes 8/1,400,090 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,444
African / African-Americangrpmax	0.00136%	73,760
South Asian	0.00111%	89,902
European (non-Finnish)	0.000445%	224,729

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro58Leu
Coding: c.173C>T
MANE Select: NM_000496
dbSNP: rs763268420
Type: single nucleotide variant
Location: chr22:25225036 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 58: the beta/gamma crystallin 'greek key' 2 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.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
CRYBB2 c.449+9G>A Benign ★★ 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-pro58leu (accessed [today's date]).

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