Is CRYGB p.Pro84= (c.252G>A) pathogenic?

CRYGB p.Pro84= (c.252G>A) is classified Uncertain significance in CRYGB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-28). Ultra-rare (popmax 0.0551%, mid); Associated with cataract 39 multiple types.

What condition is associated with CRYGB p.Pro84= (c.252G>A)?

CRYGB p.Pro84= (c.252G>A) is associated with cataract 39 multiple types (ClinVar).

How common is CRYGB p.Pro84= (c.252G>A) in the general population?

CRYGB p.Pro84= (c.252G>A) is ultra-rare (popmax 0.0551%, mid) (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.

CRYGB p.Pro84=

c.252G>A · VCV4808008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0551%, mid)

Conditions

cataract 39 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -5
Overall
CADD	0.355	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0551% Middle Eastern · 3/5,440 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.00627% 101/1,611,532 alleles · ultra-rare exomes 78/1,459,622 · genomes 23/151,910 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0551%	1,813
African / African-American	0.0441%	2,268
Admixed American	0.0133%	7,492
Remaining individualsnot grpmax-eligible	0.00802%	12,469
East Asian	0.00446%	22,400
European (non-Finnish)	0.00424%	23,577

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: CRYGB
Protein: p.Pro84=
Coding: c.252G>A
MANE Select: NM_005210
Type: single nucleotide variant
Location: chr2:208145774 (GRCh38)
Gene constraint: LOEUF 1.305 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.86 · 2 PDB
Residue 84: the 'connecting peptide' region

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

Disease context

cataract 39 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

CRYGB p.Pro84Leu Uncertain significance ★★ ⚠ same residue
CRYGB p.Ala160Pro Uncertain significance ★★ ⚠ same condition
CRYGB p.Arg116His Uncertain significance ★★ ⚠ same condition
CRYGB p.Asp95Asn Uncertain significance ★★ ⚠ same condition
CRYGB p.Ile82Val Uncertain significance ★★ ⚠ same condition
CRYGB p.Ser16Asn Uncertain significance ★★ ⚠ same condition
CRYGB p.Arg59Trp Benign ★★ same condition
CRYGB p.Ile111Leu 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/crygb-p-pro84 (accessed [today's date]).

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