Is GUCY2D p.Pro698= (c.2094G>A) pathogenic?

GUCY2D p.Pro698= (c.2094G>A) is classified Likely benign in GUCY2D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-15). Rare (popmax 0.249%, eas); Associated with Leber congenital amaurosis 1.

What condition is associated with GUCY2D p.Pro698= (c.2094G>A)?

GUCY2D p.Pro698= (c.2094G>A) is associated with Leber congenital amaurosis 1, cone-rod dystrophy 6 (ClinVar).

How common is GUCY2D p.Pro698= (c.2094G>A) in the general population?

GUCY2D p.Pro698= (c.2094G>A) is rare (popmax 0.249%, eas) (gnomAD).

How is Leber congenital amaurosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

GUCY2D p.Pro698=

c.2094G>A · rs747807494 · VCV1161383

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.249%, eas)

Conditions

Leber congenital amaurosis 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.5	GERP -3.7
Overall
CADD	2.605	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.249% East Asian · 112/44,892 alleles

Filtering AF 0.212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.198%

Overall 0.00812% 131/1,613,356 alleles · rare exomes 128/1,461,188 · genomes 3/152,168 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.249%	401
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Admixed American	0.00167%	60,010
European (non-Finnish)	0.0011%	90,749
South Asian	0.0011%	91,086

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: GUCY2D
Protein: p.Pro698=
Coding: c.2094G>A
MANE Select: NM_000180
dbSNP: rs747807494
Type: single nucleotide variant
Location: chr17:8012587 (GRCh38)
Gene constraint: LOEUF 0.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37
Residue 698: the protein kinase domain

Full GUCY2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Leber congenital amaurosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cone-rod dystrophy 6

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

GUCY2D p.Pro698Arg Uncertain significance ★★ ⚠ same residue
GUCY2D p.Pro698Leu Uncertain significance ★ ⚠ same residue
GUCY2D c.1956+1G>A Pathogenic ★★★ same condition
GUCY2D c.3224+1G>C Pathogenic ★★★ same condition
GUCY2D c.3224+3G>T Likely pathogenic ★★★ same condition
GUCY2D p.Ala946Thr Likely pathogenic ★★★ same condition
GUCY2D p.Arg1091Ter Pathogenic ★★★ same condition
GUCY2D p.Arg313Cys Likely pathogenic ★★★ ⚠ 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/gucy2d-p-pro698 (accessed [today's date]).

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