CRYGA

Chr 2

crystallin gamma A

Also known as: CRY-g-A, CRYG1, CRYG5

NCBI Gene: 1418 ENSG00000168582 UniProt: P11844 OMIM: 123660

Gamma-crystallin A is a dominant structural protein component of the vertebrate eye lens that maintains lens transparency and refractive index throughout life. Mutations cause autosomal dominant congenital cataracts, typically presenting in infancy or early childhood. This gene shows very low constraint against loss-of-function variants, suggesting tolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. Four gamma-crystallin genes (gamma-A through gamma-D) and three pseudogenes (gamma-E, gamma-F, gamma-G) are tandemly organized in a genomic segment as a gene cluster. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.82

Clinical Summary— CRYGA

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

41 VUS of 49 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.82LOEUF

pLI 0.000

Z-score -0.68

OE 1.22 (0.79–1.82)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.65Z-score

OE missense 1.17 (1.02–1.35)

136 obs / 116.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.22 (0.79–1.82)

0≤0.351.4

Missense OE?1.17 (1.02–1.35)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 13 / 10.6Missense obs/exp: 136 / 116.3Syn Z: -0.33

This gene — mechanism propensity

0.7325th %ile

GOF

0.3887th %ile

LOF

0.4726th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

49 submitted variants in ClinVar

ClinVar

Classification Summary

VUS41

Likely Benign4

Benign3

Conflicting1

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	41	0	0	41
Likely Benign	0	3	0	1	4
Benign	1	1	0	1	3
Conflicting	—				1
Total	1	45	0	2	49

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

27 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap CRYGA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →