Is GRHPR p.Arg5Gln (c.14G>A) pathogenic?

GRHPR p.Arg5Gln (c.14G>A) is classified Uncertain significance in GRHPR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-09-04). AlphaMissense: likely benign (0.1373); Very rare (popmax 0.0012%, nfe); Associated with primary hyperoxaluria type 2.

What condition is associated with GRHPR p.Arg5Gln (c.14G>A)?

GRHPR p.Arg5Gln (c.14G>A) is associated with primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Arg5Gln (c.14G>A) in the general population?

GRHPR p.Arg5Gln (c.14G>A) is very rare (popmax 0.0012%, nfe) (gnomAD).

How is Primary hyperoxaluria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GRHPR p.Arg5Gln (c.14G>A)?

AlphaMissense predicts likely benign (score 0.1373) — an in-silico prediction, not a clinical call.

GRHPR p.Arg5Gln

c.14G>A · rs760538945 · VCV991668

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1373 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0012%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary hyperoxaluria type 2

Computational evidence

Protein change
AlphaMissense	0.1373	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -1.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.4	GERP 0.068, phastCons 0.001
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	14.01	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0012% European (non-Finnish) · 14/1,171,034 alleles

Filtering AF 0.000694% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000543%

Overall 0.000879% 14/1,592,076 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.Arg5Gln
Coding: c.14G>A
MANE Select: NM_012203
dbSNP: rs760538945
Type: single nucleotide variant
Location: chr9:37422764 (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

primary hyperoxaluria type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary hyperoxaluria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Germany)

Similar variants

GRHPR p.Arg5Ter Pathogenic ★ 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-arg5gln (accessed [today's date]).

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