Is CRYBB2 p.Arg188Pro (c.563G>C) pathogenic?

CRYBB2 p.Arg188Pro (c.563G>C) is classified Likely pathogenic in CRYBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-02). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with CRYBB2-related disorder.

What condition is associated with CRYBB2 p.Arg188Pro (c.563G>C)?

CRYBB2 p.Arg188Pro (c.563G>C) is associated with CRYBB2-related disorder (ClinVar).

How common is CRYBB2 p.Arg188Pro (c.563G>C) in the general population?

CRYBB2 p.Arg188Pro (c.563G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYBB2 p.Arg188Pro (c.563G>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

CRYBB2 p.Arg188Pro

c.563G>C · VCV4947220

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CRYBB2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar · top 1% in CRYBB2
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -15.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CRYBB2
Protein: p.Arg188Pro
Coding: c.563G>C
MANE Select: NM_000496
Type: single nucleotide variant
Location: chr22:25231717 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 188: a UniProt-annotated variant site (in ctrct3); a UniProt-annotated variant site (in ctrct3; uncertain significance); a β-strand; the beta/gamma crystallin 'greek key' 4 domain

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

Disease context

CRYBB2-related disorder

Similar variants

CRYBB2 p.Arg188Cys Pathogenic/Likely pathogenic ★★ same residue
CRYBB2 p.Arg188His Pathogenic ★★ same residue
CRYBB2 p.Arg188Leu Pathogenic same residue
CRYBB2 p.Gln155Ter Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 c.173+5G>A Uncertain significance ★★ same condition
CRYBB2 p.Gln183Ter Uncertain significance ★★ same condition
CRYBB2 p.Tyr154Ter Likely pathogenic ★ same condition
CRYBB2 p.Thr150Arg 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-arg188pro (accessed [today's date]).

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