Is GUCY2D p.Asp412= (c.1236C>T) pathogenic?

GUCY2D p.Asp412= (c.1236C>T) is classified Likely benign in GUCY2D (ClinVar, Expert panel, 8 submitters; last evaluated 2025-01-30). Rare (popmax 0.129%, nfe); Associated with GUCY2D-related recessive retinopathy.

What condition is associated with GUCY2D p.Asp412= (c.1236C>T)?

GUCY2D p.Asp412= (c.1236C>T) is associated with GUCY2D-related recessive retinopathy, Leber congenital amaurosis 1, cone-rod dystrophy 6 (ClinVar).

How common is GUCY2D p.Asp412= (c.1236C>T) in the general population?

GUCY2D p.Asp412= (c.1236C>T) is rare (popmax 0.129%, nfe) (gnomAD).

GUCY2D p.Asp412=

c.1236C>T · rs61749678 · VCV98539

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.129%, nfe)

Conditions

GUCY2D-related recessive retinopathy

ClinGen expert panel — Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

Likely Benign for GUCY2D-related recessive retinopathy. Applied ACMG criteria (verbatim):

BP7 BP4

Curation rationale (ClinGen, verbatim)

NM_000180.4(GUCY2D):c.1236C>T (p.Asp412=) is a synonymous variant in exon 4 of 20. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.001028 with 1659 alleles / 1,613,498 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion. This variant has a Grpmax allele frequency of 0.001233, with 1519 alleles / 1180008 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 and fails to meet this criterion as well. The computational predictor REVEL has no data as this is a synonymous variant. The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BP4, BP7. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.11	GERP -1, phastCons 0.001
Overall
CADD	3.037	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.129% European (non-Finnish) · 1,519/1,180,008 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.121%

Overall 0.103% 1,659/1,613,498 alleles · rare exomes 1,520/1,461,172 · genomes 139/152,326 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.129%	777
Admixed American	0.0966%	1,035
Finnishnot grpmax-eligible	0.0599%	1,670
Remaining individualsnot grpmax-eligible	0.0448%	2,231
Middle Eastern	0.0334%	2,998
African / African-American	0.0147%	6,824
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
South Asian	0.0022%	45,536

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.Asp412=
Coding: c.1236C>T
MANE Select: NM_000180
dbSNP: rs61749678
Type: single nucleotide variant
Location: chr17:8006572 (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

Also linked: Leber congenital amaurosis 1 cone-rod dystrophy 6

Similar variants

GUCY2D p.Asp412Asn 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 c.722-1G>T 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-asp412 (accessed [today's date]).

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