Is CRYBA4 p.Glu73Asp (c.219A>C) pathogenic?

CRYBA4 p.Glu73Asp (c.219A>C) is classified Uncertain significance in CRYBA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-06). AlphaMissense: likely benign (0.0785); Ultra-rare (popmax 0.0267%, amr); Associated with cataract 23.

What condition is associated with CRYBA4 p.Glu73Asp (c.219A>C)?

CRYBA4 p.Glu73Asp (c.219A>C) is associated with cataract 23 (ClinVar).

How common is CRYBA4 p.Glu73Asp (c.219A>C) in the general population?

CRYBA4 p.Glu73Asp (c.219A>C) is ultra-rare (popmax 0.0267%, amr) (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 CRYBA4 p.Glu73Asp (c.219A>C)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

CRYBA4 p.Glu73Asp

c.219A>C · VCV3715282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 23

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -7.46	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 0.69	GERP -3.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,887 bp · p 0.027 · regional, not allelic
Overall
CADD	3.442	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 0.0267% Admixed American · 16/59,998 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00112% 18/1,613,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,750
European (non-Finnish)	0.000169%	590,019

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: CRYBA4
Protein: p.Glu73Asp
Coding: c.219A>C
MANE Select: NM_001886
Type: single nucleotide variant
Location: chr22:26625541 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 73: 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

cataract 23 — 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

CRYBA4 p.Glu73Lys Uncertain significance ★ ⚠ same residue
CRYBB1 p.Arg73Ter Uncertain significance ★ same residue
CRYBA4 p.Phe22Ser Uncertain significance ★★ ⚠ same condition
CRYBA4 p.Phe57Val 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

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-glu73asp (accessed [today's date]).

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