Is GRHPR p.Leu317Pro (c.950T>C) pathogenic?

GRHPR p.Leu317Pro (c.950T>C) is classified Uncertain significance in GRHPR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely pathogenic (0.962); Absent from gnomAD v4.1; Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with GRHPR p.Leu317Pro (c.950T>C)?

GRHPR p.Leu317Pro (c.950T>C) is associated with Nephrolithiasis/nephrocalcinosis (ClinVar).

How common is GRHPR p.Leu317Pro (c.950T>C) in the general population?

GRHPR p.Leu317Pro (c.950T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRHPR p.Leu317Pro (c.950T>C)?

AlphaMissense predicts likely pathogenic (score 0.962) — an in-silico prediction, not a clinical call.

GRHPR p.Leu317Pro

c.950T>C · VCV4266844

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.962 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.962	likely pathogenic · top 7% in GRHPR
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -17.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: GRHPR
Protein: p.Leu317Pro
Coding: c.950T>C
MANE Select: NM_012203
Type: single nucleotide variant
Location: chr9:37436745 (GRCh38)
Gene constraint: LOEUF 1.313 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.80 · 4 PDB
Residue 317: an α-helix

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.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
GRHPR p.Ile40Thr 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-leu317pro (accessed [today's date]).

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