Is GUCY2D p.Arg331= (c.993C>T) pathogenic?

GUCY2D p.Arg331= (c.993C>T) is classified Likely benign in GUCY2D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-16). Ultra-rare (popmax 0.0165%, mid); Associated with Leber congenital amaurosis 1.

What condition is associated with GUCY2D p.Arg331= (c.993C>T)?

GUCY2D p.Arg331= (c.993C>T) is associated with Leber congenital amaurosis 1, cone-rod dystrophy 6 (ClinVar).

How common is GUCY2D p.Arg331= (c.993C>T) in the general population?

GUCY2D p.Arg331= (c.993C>T) is ultra-rare (popmax 0.0165%, mid) (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.Arg331=

c.993C>T · rs1469682064 · VCV2926898

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Leber congenital amaurosis 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.68	GERP -2.4
Overall
CADD	3.094	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,052 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00025% 4/1,597,474 alleles · ultra-rare exomes 4/1,445,122 · genomes 0/152,352 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,052
European (non-Finnish)	0.000255%	392,523

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.Arg331=
Coding: c.993C>T
MANE Select: NM_000180
dbSNP: rs1469682064
Type: single nucleotide variant
Location: chr17:8004123 (GRCh38)
Gene constraint: LOEUF 0.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37
Residue 331: a UniProt-annotated variant site (in)

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.Arg331Ser Uncertain significance ★★ ⚠ same residue
GUCY2D p.Arg331Leu Uncertain significance ★ ⚠ same residue
GUCY2D p.Arg331Cys 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

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-arg331 (accessed [today's date]).

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