Is GRHPR p.Pro127= (c.381G>A) pathogenic?

GRHPR p.Pro127= (c.381G>A) is classified Likely benign in GRHPR (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-02). Ultra-rare (popmax 0.052%, afr); Associated with primary hyperoxaluria type 2.

What condition is associated with GRHPR p.Pro127= (c.381G>A)?

GRHPR p.Pro127= (c.381G>A) is associated with primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Pro127= (c.381G>A) in the general population?

GRHPR p.Pro127= (c.381G>A) is ultra-rare (popmax 0.052%, afr) (gnomAD).

How is Primary hyperoxaluria inherited?

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

GRHPR p.Pro127=

c.381G>A · rs151336686 · VCV1149142

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.052%, afr)

Conditions

primary hyperoxaluria type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.3	GERP -3.9
Overall
CADD	3.982	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.052% African / African-American · 39/74,962 alleles

Filtering AF 0.039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0345%

Overall 0.00571% 92/1,610,408 alleles · ultra-rare exomes 65/1,458,118 · genomes 27/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.052%	1,922
South Asian	0.0132%	7,584
Admixed American	0.01%	10,003
Remaining individualsnot grpmax-eligible	0.00481%	20,788
European (non-Finnish)	0.00263%	37,958
East Asian	0.00223%	44,862

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.Pro127=
Coding: c.381G>A
MANE Select: NM_012203
dbSNP: rs151336686
Type: single nucleotide variant
Location: chr9:37426631 (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 127: an α-helix

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.Pro127Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro127 (accessed [today's date]).

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