Is GUCY2D p.Val757= (c.2271G>A) pathogenic?

GUCY2D p.Val757= (c.2271G>A) is classified Likely benign in GUCY2D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-11). Very rare (popmax 0.00667%, afr); Associated with cone-rod dystrophy 6.

What condition is associated with GUCY2D p.Val757= (c.2271G>A)?

GUCY2D p.Val757= (c.2271G>A) is associated with cone-rod dystrophy 6, Leber congenital amaurosis 1 (ClinVar).

How common is GUCY2D p.Val757= (c.2271G>A) in the general population?

GUCY2D p.Val757= (c.2271G>A) is very rare (popmax 0.00667%, afr) (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.Val757=

c.2271G>A · rs143607596 · VCV1135258

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

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 1.2	GERP -3, phastCons 1
Overall
CADD	15.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,930 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000682% 11/1,613,428 alleles · very rare exomes 6/1,461,210 · genomes 5/152,218 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,986
European (non-Finnish)	0.000509%	196,591

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.Val757=
Coding: c.2271G>A
MANE Select: NM_000180
dbSNP: rs143607596
Type: single nucleotide variant
Location: chr17:8013887 (GRCh38)
Gene constraint: LOEUF 0.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.37
Residue 757: the protein kinase domain

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.Val757del 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
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-val757 (accessed [today's date]).

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