Is CRYBA4 p.Leu69Pro (c.206T>C) pathogenic?

CRYBA4 p.Leu69Pro (c.206T>C) is classified Likely pathogenic in CRYBA4 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-18). AlphaMissense: likely pathogenic (0.97); Absent from gnomAD v4.1; Associated with CRYBA4-related disorders.

What condition is associated with CRYBA4 p.Leu69Pro (c.206T>C)?

CRYBA4 p.Leu69Pro (c.206T>C) is associated with CRYBA4-related disorders, cataract 23 (ClinVar).

How common is CRYBA4 p.Leu69Pro (c.206T>C) in the general population?

CRYBA4 p.Leu69Pro (c.206T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYBA4 p.Leu69Pro (c.206T>C)?

AlphaMissense predicts likely pathogenic (score 0.97) — an in-silico prediction, not a clinical call.

CRYBA4 p.Leu69Pro

c.206T>C · rs74315487 · VCV16947

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.97 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CRYBA4-related disorders

Computational evidence

Protein change
AlphaMissense	0.97	likely pathogenic ✓ concordant with ClinVar · top 4% in CRYBA4
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -14.96	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 7.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,887 bp · p 0.027 · regional, not allelic
Overall
CADD	24.0	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: CRYBA4
Protein: p.Leu69Pro
Coding: c.206T>C
MANE Select: NM_001886
dbSNP: rs74315487
Type: single nucleotide variant
Location: chr22:26625528 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 69: a UniProt-annotated variant site (in ctrct23; the patient has cataract and bilateral microphthalmia; the mutation is predicted to disrupt the beta-sheet structure of the protein); a β-strand; the beta/gamma crystallin 'greek key' 2 domain

Full CRYBA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CRYBA4-related disorders

Also linked: cataract 23

Similar variants

CRYBA4 p.Phe22Ser Uncertain significance ★★ ⚠ same condition
CRYBA4 p.Phe57Val Uncertain significance ★★ ⚠ same condition
CRYBB1 p.Arg233Cys Uncertain significance ★★ ⚠ same condition
CRYBA4 c.159-20A>G Benign ★★ same condition
CRYBA4 c.300+3A>G Benign ★★ same condition
CRYBA4 c.40-1G>C Benign/Likely benign ★★ same condition
CRYBA4 c.444-18G>A Benign ★★ same condition
CRYBA4 p.Arg103Cys Benign/Likely 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/cryba4-p-leu69pro (accessed [today's date]).

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