Is GUCY2C p.Arg686Pro (c.2057G>C) pathogenic?

GUCY2C p.Arg686Pro (c.2057G>C) is classified Uncertain significance in GUCY2C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely benign (0.2185); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with GUCY2C p.Arg686Pro (c.2057G>C)?

GUCY2C p.Arg686Pro (c.2057G>C) is associated with Inborn genetic diseases (ClinVar).

How common is GUCY2C p.Arg686Pro (c.2057G>C) in the general population?

GUCY2C p.Arg686Pro (c.2057G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GUCY2C p.Arg686Pro (c.2057G>C)?

AlphaMissense predicts likely benign (score 0.2185) — an in-silico prediction, not a clinical call.

GUCY2C p.Arg686Pro

c.2057G>C · rs769986387 · VCV2618684

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2185 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2185	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -2.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.84, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 83 kb · p 7.2e-05 · regional, not allelic
Overall
CADD	19.92	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GUCY2C
Protein: p.Arg686Pro
Coding: c.2057G>C
MANE Select: NM_004963
dbSNP: rs769986387
Type: single nucleotide variant
Location: chr12:14641093 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 80.08 · 3 PDB
Residue 686: the protein kinase domain

Full GUCY2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GUCY2C p.Arg686Gln Uncertain significance ★★ ⚠ same residue
GUCY2C p.Arg686Trp Uncertain significance ★★ ⚠ same residue
GUCY2C p.Ala450Thr Uncertain significance ★★ ⚠ same condition
GUCY2C p.Ala897Thr Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg1021Cys Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg114Trp Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg319Gln Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg570Gln Uncertain significance ★★ ⚠ 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/gucy2c-p-arg686pro (accessed [today's date]).

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