Is CRYBB3 p.His113Asp (c.337C>G) pathogenic?

CRYBB3 p.His113Asp (c.337C>G) is classified Benign in CRYBB3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0558); Common (popmax 92.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with cataract 22 multiple types.

What condition is associated with CRYBB3 p.His113Asp (c.337C>G)?

CRYBB3 p.His113Asp (c.337C>G) is associated with cataract 22 multiple types (ClinVar).

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.His113Asp (c.337C>G)?

AlphaMissense predicts likely benign (score 0.0558) — an in-silico prediction, not a clinical call.

CRYBB3 p.His113Asp

Q: How common is CRYBB3 p.His113Asp (c.337C>G) in the general population?

CRYBB3 p.His113Asp (c.337C>G) is common (popmax 92.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.337C>G · rs9608378 · VCV259229

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0558 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 92.2%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 22 multiple types

Computational evidence

Protein change
AlphaMissense	0.0558	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -2.04	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 8.3	GERP -0.48, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	15.22	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 92.2% East Asian · 41,348/44,834 alleles

Filtering AF 91.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 91.2%

Overall 63.2% 1,020,256/1,613,446 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	92.2%	1
Admixed American	74%	1
Amishnot grpmax-eligible	70.3%	1
Ashkenazi Jewishnot grpmax-eligible	68.3%	1
South Asian	68.2%	1
Remaining individualsnot grpmax-eligible	64.5%	2
Middle Eastern	63.9%	2
European (non-Finnish)	62.4%	2
Finnishnot grpmax-eligible	58.5%	2
African / African-American	45%	2

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.His113Asp
Coding: c.337C>G
MANE Select: NM_004076
dbSNP: rs9608378
Type: single nucleotide variant
Location: chr22:25205229 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 113: a UniProt-annotated variant site (in); the 'connecting peptide' 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.His113Gln 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
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-his113asp (accessed [today's date]).

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