Is CRYBB3 p.Arg75His (c.224G>A) pathogenic?

CRYBB3 p.Arg75His (c.224G>A) is classified Uncertain significance in CRYBB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.0758); Ultra-rare (popmax 0.0889%, sas); Associated with cataract 22 multiple types.

What condition is associated with CRYBB3 p.Arg75His (c.224G>A)?

CRYBB3 p.Arg75His (c.224G>A) is associated with cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Arg75His (c.224G>A) in the general population?

CRYBB3 p.Arg75His (c.224G>A) is ultra-rare (popmax 0.0889%, sas) (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.Arg75His (c.224G>A)?

AlphaMissense predicts likely benign (score 0.0758) — an in-silico prediction, not a clinical call.

CRYBB3 p.Arg75His

c.224G>A · rs183587921 · VCV902429

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0758 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0889%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cataract 22 multiple types

Computational evidence

Protein change
AlphaMissense	0.0758	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.81, phastCons 0.012
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	17.79	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0889% South Asian · 81/91,084 alleles

Filtering AF 0.0733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0675%

Overall 0.0351% 566/1,614,186 alleles · ultra-rare exomes 533/1,461,878 · genomes 33/152,308 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0889%	1,124
Finnishnot grpmax-eligible	0.0625%	1,601
Remaining individualsnot grpmax-eligible	0.0448%	2,233
East Asian	0.0334%	2,992
European (non-Finnish)	0.0331%	3,018
Admixed American	0.0133%	7,504
African / African-American	0.004%	25,016

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.Arg75His
Coding: c.224G>A
MANE Select: NM_004076
dbSNP: rs183587921
Type: single nucleotide variant
Location: chr22:25203792 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 75: a UniProt-annotated variant site (in ctrct22; uncertain significance); the beta/gamma crystallin 'greek key' 2 domain

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.Arg75Cys Uncertain significance ★★ ⚠ same residue
CRYBB3 p.Arg75Leu 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.Arg207His 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-arg75his (accessed [today's date]).

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