Is GUCY2C p.Pro429= (c.1287T>C) pathogenic?

GUCY2C p.Pro429= (c.1287T>C) is classified Likely benign in GUCY2C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-20). Very rare (popmax 0.00267%, afr).

How common is GUCY2C p.Pro429= (c.1287T>C) in the general population?

GUCY2C p.Pro429= (c.1287T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

GUCY2C p.Pro429=

c.1287T>C · rs553517128 · VCV2881035

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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 0.88	GERP -3.5, phastCons 0.98
Overall
CADD	7.513	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,920 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,609,112 alleles · very rare exomes 0/1,456,806 · genomes 2/152,306 · joint denominator

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: GUCY2C
Protein: p.Pro429=
Coding: c.1287T>C
MANE Select: NM_004963
dbSNP: rs553517128
Type: single nucleotide variant
Location: chr12:14661058 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 80.08 · 3 PDB

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

Similar variants

GUCY2C p.Pro429Leu Uncertain significance ★ ⚠ same residue
GUCY2C p.Asp387Gly Pathogenic ★★ ⚠ same type
GUCY2C c.2602-1G>C Uncertain significance ★★ same type
GUCY2C c.2776+5G>A Uncertain significance ★★ same type
GUCY2C c.612-1G>A Uncertain significance ★★ same type
GUCY2C p.Ala450Thr Uncertain significance ★★ ⚠ same type
GUCY2C p.Ala48Gly Uncertain significance ★★ ⚠ same type
GUCY2C p.Ala670Thr Uncertain significance ★★ ⚠ same type

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-pro429 (accessed [today's date]).

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