CRYGD

Chr 2AD

crystallin gamma D

Also known as: CACA, CCA3, CCP, CRYG4, CTRCT4, PCC, cry-g-D

NCBI Gene: 1421 ENSG00000118231 UniProt: P07320 OMIM: 123690

Gamma-D crystallin is a structural protein that maintains lens transparency and refractive index in the eye. Mutations in CRYGD cause congenital cataracts, which can present at birth or in early childhood and may lead to visual impairment if untreated. The inheritance pattern is autosomal dominant.

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…

LOFmechanismADLOEUF 1.501 OMIM phenotype

Clinical Summary— CRYGD

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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

17 unique Pathogenic / Likely Pathogenic· 43 VUS of 99 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.50LOEUF

pLI 0.000

Z-score 0.58

OE 0.77 (0.42–1.50)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.08Z-score

OE missense 0.98 (0.83–1.15)

106 obs / 108.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.77 (0.42–1.50)

0≤0.351.4

Missense OE?0.98 (0.83–1.15)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 6 / 7.8Missense obs/exp: 106 / 108.4Syn Z: -0.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCRYGD-related cataractLOFAD

This gene — mechanism propensity

0.79top 25%

GOF

0.4283th %ile

LOF

0.3744th %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

99 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic11

VUS43

Likely Benign12

Benign23

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	4	0	0	6
Likely Pathogenic	6	5	0	0	11
VUS	6	34	1	2	43
Likely Benign	0	4	3	5	12
Benign	0	3	16	4	23
Conflicting	—				4
Total	14	50	20	11	99

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap CRYGD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →