Is GUCY2D p.Pro127= (c.381G>A) pathogenic?

GUCY2D p.Pro127= (c.381G>A) is classified Likely benign in GUCY2D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-25). Very rare (popmax 0.00243%, sas); Associated with cone-rod dystrophy 6.

What condition is associated with GUCY2D p.Pro127= (c.381G>A)?

GUCY2D p.Pro127= (c.381G>A) is associated with cone-rod dystrophy 6, Leber congenital amaurosis 1 (ClinVar).

How common is GUCY2D p.Pro127= (c.381G>A) in the general population?

GUCY2D p.Pro127= (c.381G>A) is very rare (popmax 0.00243%, sas) (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.Pro127=

c.381G>A · rs1400180995 · VCV1496118

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00243%, sas)

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 -5	GERP -2.8
Overall
CADD	5.715	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00243% South Asian · 2/82,344 alleles

Filtering AF 0.00127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00165% 25/1,512,828 alleles · very rare exomes 24/1,360,762 · genomes 1/152,066 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00243%	41,172
European (non-Finnish)	0.00193%	51,702
Remaining individualsnot grpmax-eligible	0.0017%	58,666

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.Pro127=
Coding: c.381G>A
MANE Select: NM_000180
dbSNP: rs1400180995
Type: single nucleotide variant
Location: chr17:8003428 (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

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.Pro127Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
GUCY2D p.Pro127Arg 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

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-pro127 (accessed [today's date]).

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