Is GUCY2D p.Ser115Pro (c.343T>C) pathogenic?

GUCY2D p.Ser115Pro (c.343T>C) is classified Conflicting classifications of pathogenicity in GUCY2D (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.1048); Rare (popmax 0.224%, eas); Associated with cone-rod dystrophy 6.

What condition is associated with GUCY2D p.Ser115Pro (c.343T>C)?

GUCY2D p.Ser115Pro (c.343T>C) is associated with cone-rod dystrophy 6, Leber congenital amaurosis 1 (ClinVar).

How common is GUCY2D p.Ser115Pro (c.343T>C) in the general population?

GUCY2D p.Ser115Pro (c.343T>C) is rare (popmax 0.224%, eas) (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.Ser115Pro (c.343T>C)?

AlphaMissense predicts likely benign (score 0.1048) — an in-silico prediction, not a clinical call.

GUCY2D p.Ser115Pro

c.343T>C · rs562248093 · VCV866021

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1048 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.224%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cone-rod dystrophy 6

Computational evidence

Protein change
AlphaMissense	0.1048	likely benign
REVEL	0.296	indeterminate
SaProt	LLR -10.54	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -2.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 12 kb · p 0.34 · regional, not allelic
Overall
CADD	20.4	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 0.224% East Asian · 77/34,410 alleles

Filtering AF 0.183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.169%

Overall 0.0134% 198/1,475,088 alleles · rare exomes 159/1,323,032 · genomes 39/152,056 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.224%	447
Remaining individualsnot grpmax-eligible	0.0299%	3,339
European (non-Finnish)	0.00866%	11,550
South Asian	0.0077%	12,981
Finnishnot grpmax-eligible	0.00227%	44,092

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.Ser115Pro
Coding: c.343T>C
MANE Select: NM_000180
dbSNP: rs562248093
Type: single nucleotide variant
Location: chr17:8003390 (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 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-ser115pro (accessed [today's date]).

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