Is GRHPR p.Pro3= (c.9G>C) pathogenic?

GRHPR p.Pro3= (c.9G>C) is classified Likely benign in GRHPR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-18). Very rare (popmax 0.000856%, nfe); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with GRHPR p.Pro3= (c.9G>C)?

GRHPR p.Pro3= (c.9G>C) is associated with Nephrolithiasis/nephrocalcinosis (ClinVar).

How common is GRHPR p.Pro3= (c.9G>C) in the general population?

GRHPR p.Pro3= (c.9G>C) is very rare (popmax 0.000856%, nfe) (gnomAD).

GRHPR p.Pro3=

c.9G>C · rs1383422680 · VCV1086804

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000856%, nfe)

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.22	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP -7	GERP -4.2
Overall
CADD	0.405	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000856% European (non-Finnish) · 10/1,168,692 alleles

Filtering AF 0.000433% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000315%

Overall 0.000697% 10/1,435,606 alleles · very rare

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: GRHPR
Protein: p.Pro3=
Coding: c.9G>C
MANE Select: NM_012203
dbSNP: rs1383422680
Type: single nucleotide variant
Location: chr9:37422759 (GRCh38)
Gene constraint: LOEUF 1.313 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.80 · 4 PDB

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

Disease context

Nephrolithiasis/nephrocalcinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GRHPR p.Pro3Leu Uncertain significance ★★ ⚠ same residue
GRHPR p.Ala169Pro Uncertain significance ★★ ⚠ same condition
GRHPR p.Arg185Cys Uncertain significance ★★ ⚠ same condition
GRHPR p.Arg99Gln Uncertain significance ★★ ⚠ same condition
GRHPR p.Gly176Ser Uncertain significance ★★ ⚠ same condition
GRHPR p.Gly54Ser Uncertain significance ★★ ⚠ same condition
GRHPR p.Ile164Val Uncertain significance ★★ ⚠ same condition
GRHPR p.Ile263Thr 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/grhpr-p-pro3 (accessed [today's date]).

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