Is GUCY2D p.Pro1065= (c.3195C>G) pathogenic?

GUCY2D p.Pro1065= (c.3195C>G) is classified Likely benign in GUCY2D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-05). Very rare (popmax 0.00229%, eas); Associated with cone-rod dystrophy 6.

What condition is associated with GUCY2D p.Pro1065= (c.3195C>G)?

GUCY2D p.Pro1065= (c.3195C>G) is associated with cone-rod dystrophy 6, Leber congenital amaurosis 1 (ClinVar).

How common is GUCY2D p.Pro1065= (c.3195C>G) in the general population?

GUCY2D p.Pro1065= (c.3195C>G) is very rare (popmax 0.00229%, eas) (gnomAD).

How is Cone rod dystrophy inherited?

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

GUCY2D p.Pro1065=

c.3195C>G · rs765119055 · VCV1460598

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00229%, eas)

Conditions

cone-rod dystrophy 6

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 -0.71	GERP -3.7, phastCons 0.01
Overall
CADD	13.72	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% East Asian · 1/43,680 alleles

Filtering AF 0.00131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0011%

Overall 0.00177% 28/1,582,410 alleles · very rare exomes 23/1,430,226 · genomes 5/152,184 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00326%	30,660
East Asiangrpmax	0.00229%	43,680
European (non-Finnish)	0.00197%	50,640
Admixed American	0.00184%	54,324
African / African-American	0.00134%	74,588

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1065=
Coding: c.3195C>G
MANE Select: NM_000180
dbSNP: rs765119055
Type: single nucleotide variant
Location: chr17:8016261 (GRCh38)
Gene constraint: LOEUF 0.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37
Residue 1065: the 'disordered' region

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

Disease context

cone-rod dystrophy 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leber congenital amaurosis 1

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
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-pro1065 (accessed [today's date]).

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