Is GRHPR p.Arg124Cys (c.370C>T) pathogenic?

GRHPR p.Arg124Cys (c.370C>T) is classified Likely pathogenic in GRHPR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.7055); Very rare (popmax 0.0011%, sas); Associated with GRHPR-related disorders.

What condition is associated with GRHPR p.Arg124Cys (c.370C>T)?

GRHPR p.Arg124Cys (c.370C>T) is associated with GRHPR-related disorders, primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Arg124Cys (c.370C>T) in the general population?

GRHPR p.Arg124Cys (c.370C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about GRHPR p.Arg124Cys (c.370C>T)?

AlphaMissense predicts likely pathogenic (score 0.7055) — an in-silico prediction, not a clinical call.

GRHPR p.Arg124Cys

c.370C>T · rs372712521 · VCV2078815

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7055 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GRHPR-related disorders

Computational evidence

Protein change
AlphaMissense	0.7055	likely pathogenic ✓ concordant with ClinVar
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -15.25	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 7.6	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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,062 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000616% 9/1,460,786 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,986
South Asiangrpmax	0.0011%	91,062
European (non-Finnish)	0.000509%	196,513

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg124Cys
Coding: c.370C>T
MANE Select: NM_012203
dbSNP: rs372712521
Type: single nucleotide variant
Location: chr9:37426620 (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

GRHPR-related disorders

Also linked: primary hyperoxaluria type 2

Similar variants

GRHPR p.Arg124His Uncertain significance ★ ⚠ same residue
GRHPR c.404+5G>A Likely pathogenic ★★ same condition
GRHPR c.493+2T>A Pathogenic/Likely pathogenic ★★ same condition
GRHPR c.494-2A>G Pathogenic/Likely pathogenic ★★ same condition
GRHPR c.734+1G>A Pathogenic/Likely pathogenic ★★ same condition
GRHPR c.735-1G>A Pathogenic/Likely pathogenic ★★ same condition
GRHPR c.83+1G>C Pathogenic/Likely pathogenic ★★ same condition
GRHPR c.84-2A>G Pathogenic ★★ 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-arg124cys (accessed [today's date]).

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