Is CRYBA2 c.446+1G>A pathogenic?

CRYBA2 c.446+1G>A is classified Uncertain significance in CRYBA2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-03-17). Ultra-rare (popmax 0.0407%, nfe); Associated with cataract 42.

What condition is associated with CRYBA2 c.446+1G>A?

CRYBA2 c.446+1G>A is associated with cataract 42 (ClinVar).

How common is CRYBA2 c.446+1G>A in the general population?

CRYBA2 c.446+1G>A is ultra-rare (popmax 0.0407%, nfe) (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.

CRYBA2 c.446+1G>A

VCV3893078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0407%, nfe)

Conditions

cataract 42

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	Δ0.98	donor loss · deltas
Pangolin	Δ0.76	loss · gain 0.19 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.7	GERP 0.9, phastCons 1
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0407% European (non-Finnish) · 480/1,178,928 alleles

Filtering AF 0.0377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.0362% 584/1,612,740 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.183%	548
Remaining individualsnot grpmax-eligible	0.0592%	1,688
European (non-Finnish)grpmax	0.0407%	2,456
Middle Eastern	0.0165%	6,054
African / African-American	0.0107%	9,377
Finnishnot grpmax-eligible	0.00312%	32,004
East Asian	0.00223%	44,818
South Asian	0.0011%	90,990

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CRYBA2
Coding: c.446+1G>A
MANE Select: NM_057093
Type: single nucleotide variant
Location: chr2:218990851 (GRCh38)
Gene constraint: LOEUF 1.372 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.12

Full CRYBA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 42 — 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

CRYBA2 c.303+5G>A Uncertain significance ★ same condition
CRYBA2 p.Ala80Thr Uncertain significance ★★ ⚠ same type
CRYBA2 c.303+127A>G Benign ★★ same type
CRYBA2 c.304-16T>C Benign ★★ same type
CRYBA2 p.Ala10Pro Uncertain significance ★ ⚠ same type
CRYBA2 p.Ala34Glu Uncertain significance ★ ⚠ same type
CRYBA2 p.Ala6Ser Uncertain significance ★ ⚠ same type
CRYBA2 p.Arg107Cys Uncertain significance ★ ⚠ same type

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/cryba2-c-446-plus-1g-a (accessed [today's date]).

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