GUCA1C

Chr 3

guanylate cyclase activator 1C

Also known as: GCAP3

NCBI Gene: 9626 ENSG00000138472 UniProt: O95843 OMIM: 605128

The protein functions as a calcium-sensitive regulator of guanylyl cyclases in rod photoreceptors, stimulating these enzymes at low calcium concentrations and inhibiting them at high calcium concentrations to enable recovery of the dark state following light exposure. Mutations cause autosomal recessive cone-rod dystrophy, a retinal degeneration affecting both cone and rod photoreceptors. This gene shows low constraint against loss-of-function variants, consistent with recessive inheritance where both copies must be affected to cause disease.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable calcium ion binding activity and calcium sensitive guanylate cyclase activator activity. Predicted to be involved in regulation of signal transduction. Predicted to be located in photoreceptor disc membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.88

Clinical Summary— GUCA1C

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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

33 VUS of 44 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?

1.88LOEUF

pLI 0.000

Z-score -0.67

OE 1.27 (0.75–1.88)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.32Z-score

OE missense 1.09 (0.93–1.27)

116 obs / 106.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.27 (0.75–1.88)

0≤0.351.4

Missense OE?1.09 (0.93–1.27)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 9 / 7.1Missense obs/exp: 116 / 106.8Syn Z: 0.76

This gene — mechanism propensity

0.77top 25%

GOF

0.81top 10%

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

44 submitted variants in ClinVar

ClinVar

Classification Summary

VUS33

Likely Benign3

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	32	1	33
Likely Benign	3	0	3
Benign	0	0	0
Total	35	1	36

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap GUCA1C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →