Is CRYBB3 p.Arg207Cys (c.619C>T) pathogenic?

CRYBB3 p.Arg207Cys (c.619C>T) is classified Conflicting classifications of pathogenicity in CRYBB3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.0616); Ultra-rare (popmax 0.0111%, eas); Associated with cataract 22 multiple types.

What condition is associated with CRYBB3 p.Arg207Cys (c.619C>T)?

CRYBB3 p.Arg207Cys (c.619C>T) is associated with cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Arg207Cys (c.619C>T) in the general population?

CRYBB3 p.Arg207Cys (c.619C>T) is ultra-rare (popmax 0.0111%, eas) (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.

What do computational predictors say about CRYBB3 p.Arg207Cys (c.619C>T)?

AlphaMissense predicts likely benign (score 0.0616) — an in-silico prediction, not a clinical call.

CRYBB3 p.Arg207Cys

c.619C>T · VCV4007160

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0616 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 22 multiple types

Computational evidence

Protein change
AlphaMissense	0.0616	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -3.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.059	GERP -0.56, phastCons 0.95
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	13.15	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 0.0111% East Asian · 5/44,866 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00093% 15/1,612,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,973
African / African-American	0.00534%	18,726
South Asian	0.0011%	91,028
European (non-Finnish)	0.000424%	235,915

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.Arg207Cys
Coding: c.619C>T
MANE Select: NM_004076
Type: single nucleotide variant
Location: chr22:25207195 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 207: the 'c-terminal arm' region

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.Arg207His Uncertain significance ★★ ⚠ same residue
CRYBB3 p.Arg207= Uncertain significance ★ same residue
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.Arg75Cys 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-arg207cys (accessed [today's date]).

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