Is GRHPR p.Cys57Ser (c.170G>C) pathogenic?

GRHPR p.Cys57Ser (c.170G>C) is classified Uncertain significance in GRHPR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.7971); Very rare (popmax 0.000339%, nfe); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with GRHPR p.Cys57Ser (c.170G>C)?

GRHPR p.Cys57Ser (c.170G>C) is associated with Nephrolithiasis/nephrocalcinosis (ClinVar).

How common is GRHPR p.Cys57Ser (c.170G>C) in the general population?

GRHPR p.Cys57Ser (c.170G>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about GRHPR p.Cys57Ser (c.170G>C)?

AlphaMissense predicts likely pathogenic (score 0.7971) — an in-silico prediction, not a clinical call.

GRHPR p.Cys57Ser

c.170G>C · VCV4266846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.7971	likely pathogenic
REVEL	0.565	indeterminate
SaProt	LLR -11.44	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	29.6	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

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,892 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,612,268 alleles · very rare exomes 3/1,460,082 · genomes 1/152,186 · 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: GRHPR
Protein: p.Cys57Ser
Coding: c.170G>C
MANE Select: NM_012203
Type: single nucleotide variant
Location: chr9:37424931 (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 57: 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.Cys57Tyr Likely pathogenic ★ 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-cys57ser (accessed [today's date]).

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