Is CRYBB2 p.Ser143Pro (c.427T>C) pathogenic?

CRYBB2 p.Ser143Pro (c.427T>C) is classified Likely pathogenic in CRYBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-19). AlphaMissense: likely pathogenic (0.9973); Absent from gnomAD v4.1; Associated with cataract 3 multiple types.

What condition is associated with CRYBB2 p.Ser143Pro (c.427T>C)?

CRYBB2 p.Ser143Pro (c.427T>C) is associated with cataract 3 multiple types (ClinVar).

How common is CRYBB2 p.Ser143Pro (c.427T>C) in the general population?

CRYBB2 p.Ser143Pro (c.427T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYBB2 p.Ser143Pro (c.427T>C)?

AlphaMissense predicts likely pathogenic (score 0.9973) — an in-silico prediction, not a clinical call.

CRYBB2 p.Ser143Pro

c.427T>C · rs2517857101 · VCV1803265

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9973 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 3 multiple types

Computational evidence

Protein change
AlphaMissense	0.9973	likely pathogenic ✓ concordant with ClinVar · top 1% in CRYBB2
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -15.48	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 6.1	GERP -2.5, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	28.4	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.Ser143Pro
Coding: c.427T>C
MANE Select: NM_000496
dbSNP: rs2517857101
Type: single nucleotide variant
Location: chr22:25229556 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 143: 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.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-ser143pro (accessed [today's date]).

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