Is GRHPR p.Arg99Leu (c.296G>T) pathogenic?

GRHPR p.Arg99Leu (c.296G>T) is classified Uncertain significance in GRHPR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-15). AlphaMissense: likely benign (0.3377); Absent from gnomAD v4.1; Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with GRHPR p.Arg99Leu (c.296G>T)?

GRHPR p.Arg99Leu (c.296G>T) is associated with Nephrolithiasis/nephrocalcinosis (ClinVar).

How common is GRHPR p.Arg99Leu (c.296G>T) in the general population?

GRHPR p.Arg99Leu (c.296G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRHPR p.Arg99Leu (c.296G>T)?

AlphaMissense predicts likely benign (score 0.3377) — an in-silico prediction, not a clinical call.

GRHPR p.Arg99Leu

c.296G>T · VCV3855694

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3377 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,606,400)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.3377	likely benign
REVEL	0.561	indeterminate
SaProt	LLR -13.33	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	34.0	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

No allele count reported in gnomAD v4.1 (AN 1,606,400). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: GRHPR
Protein: p.Arg99Leu
Coding: c.296G>T
MANE Select: NM_012203
Type: single nucleotide variant
Location: chr9:37426546 (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 99: a β-strand

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.Arg99Gln Uncertain significance ★★ ⚠ same residue
GRHPR p.Arg99Ter Pathogenic ★★ same residue
GRHPR p.Ala169Pro Uncertain significance ★★ ⚠ same condition
GRHPR p.Arg185Cys 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-arg99leu (accessed [today's date]).

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