Is GUCY2D p.Pro1069Ser (c.3205C>T) pathogenic?

GUCY2D p.Pro1069Ser (c.3205C>T) is classified Uncertain significance in GUCY2D (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-17). AlphaMissense: likely pathogenic (0.9641); Very rare (popmax 6.34e-05%); Associated with cone-rod dystrophy 6.

What condition is associated with GUCY2D p.Pro1069Ser (c.3205C>T)?

GUCY2D p.Pro1069Ser (c.3205C>T) is associated with cone-rod dystrophy 6, Leber congenital amaurosis 1 (ClinVar).

How common is GUCY2D p.Pro1069Ser (c.3205C>T) in the general population?

GUCY2D p.Pro1069Ser (c.3205C>T) is very rare (popmax 6.34e-05%) (gnomAD).

How is Cone rod dystrophy 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.Pro1069Ser (c.3205C>T)?

AlphaMissense predicts likely pathogenic (score 0.9641) — an in-silico prediction, not a clinical call.

GUCY2D p.Pro1069Ser

c.3205C>T · rs1187326101 · VCV1525273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.34e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cone-rod dystrophy 6

Computational evidence

Protein change
AlphaMissense	0.9641	likely pathogenic · top 10% in GUCY2D
REVEL	0.463	indeterminate
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.49, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,122 bp · p 0.39 · regional, not allelic
Overall
CADD	28.4	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 6.34e-05%

Overall 6.34e-05% 1/1,576,776 alleles · very rare exomes 0/1,424,556 · genomes 1/152,220 · 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.Pro1069Ser
Coding: c.3205C>T
MANE Select: NM_000180
dbSNP: rs1187326101
Type: single nucleotide variant
Location: chr17:8016271 (GRCh38)
Gene constraint: LOEUF 0.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37
Residue 1069: 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 p.Pro1069= Likely benign ★ 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
GUCY2D p.Arg521Ter 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-pro1069ser (accessed [today's date]).

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