Is GUCY2D p.Pro94Arg (c.281C>G) pathogenic?

GUCY2D p.Pro94Arg (c.281C>G) is classified Uncertain significance in GUCY2D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely benign (0.2574); Very rare (popmax 0.000445%, nfe); Associated with Leber congenital amaurosis 1.

What condition is associated with GUCY2D p.Pro94Arg (c.281C>G)?

GUCY2D p.Pro94Arg (c.281C>G) is associated with Leber congenital amaurosis 1, cone-rod dystrophy 6 (ClinVar).

How common is GUCY2D p.Pro94Arg (c.281C>G) in the general population?

GUCY2D p.Pro94Arg (c.281C>G) is very rare (popmax 0.000445%, nfe) (gnomAD).

How is Leber congenital amaurosis inherited?

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

What do computational predictors say about GUCY2D p.Pro94Arg (c.281C>G)?

AlphaMissense predicts likely benign (score 0.2574) — an in-silico prediction, not a clinical call.

GUCY2D p.Pro94Arg

c.281C>G · VCV4792052

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000445%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Leber congenital amaurosis 1

Computational evidence

Protein change
AlphaMissense	0.2574	likely benign
REVEL	0.318	indeterminate
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.84, phastCons 0.37
Regional constraint	o/e 0.97	unconstrained · MANE · 12 kb · p 0.34 · regional, not allelic
Overall
CADD	16.21	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000445% European (non-Finnish) · 5/1,123,634 alleles

Filtering AF 0.00013% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.5e-05%

Overall 0.000337% 5/1,482,924 alleles · very rare exomes 3/1,330,838 · genomes 2/152,086 · joint denominator

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.Pro94Arg
Coding: c.281C>G
MANE Select: NM_000180
Type: single nucleotide variant
Location: chr17:8003328 (GRCh38)
Gene constraint: LOEUF 0.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37

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 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
GUCY2D p.Arg521Ter Pathogenic ★★★ same condition
GUCY2D p.Arg588Trp 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-pro94arg (accessed [today's date]).

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