Is GRHPR p.Met1Val (c.1A>G) pathogenic?

GRHPR p.Met1Val (c.1A>G) is classified Pathogenic in GRHPR (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-22). Very rare (popmax 0.00345%, sas); Associated with primary hyperoxaluria type 2.

What condition is associated with GRHPR p.Met1Val (c.1A>G)?

GRHPR p.Met1Val (c.1A>G) is associated with primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Met1Val (c.1A>G) in the general population?

GRHPR p.Met1Val (c.1A>G) is very rare (popmax 0.00345%, sas) (gnomAD).

How is Primary hyperoxaluria inherited?

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

GRHPR p.Met1Val

c.1A>G · rs1554746094 · VCV554025

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00345%, sas)

Conditions

primary hyperoxaluria type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.436	indeterminate
Splicing
SpliceAI	Δ0.53	donor gain · deltas
Constraint at this position
Conservation	phyloP 3.1	GERP 2.1, phastCons 0.98
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00345% South Asian · 3/86,852 alleles

Filtering AF 0.000917% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000454%

Overall 0.000489% 7/1,430,106 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00345%	28,951
European (non-Finnish)	0.000343%	291,465

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.Met1Val
Coding: c.1A>G
MANE Select: NM_012203
dbSNP: rs1554746094
Type: single nucleotide variant
Location: chr9:37422751 (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.Met1Arg Likely pathogenic same residue
GRHPR p.Met1Leu Likely 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

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-met1val (accessed [today's date]).

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