Is GRHPR p.Pro321= (c.963G>A) pathogenic?

GRHPR p.Pro321= (c.963G>A) is classified Benign/Likely benign in GRHPR (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-31). Low-frequency (popmax 2.5%, afr); Associated with primary hyperoxaluria type 2.

What condition is associated with GRHPR p.Pro321= (c.963G>A)?

GRHPR p.Pro321= (c.963G>A) is associated with primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Pro321= (c.963G>A) in the general population?

GRHPR p.Pro321= (c.963G>A) is low-frequency (popmax 2.5%, afr) (gnomAD).

How is Primary hyperoxaluria inherited?

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

GRHPR p.Pro321=

c.963G>A · rs76299266 · VCV204229

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.5%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.7	GERP -4.1
Overall
CADD	8.839	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.5% African / African-American · 1,875/75,012 alleles

Filtering AF 2.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.37%

Overall 0.661% 10,674/1,614,002 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.5%	40
South Asian	2.09%	48
Middle Eastern	1.57%	64
Remaining individualsnot grpmax-eligible	0.662%	151
European (non-Finnish)	0.486%	206
Finnishnot grpmax-eligible	0.45%	222
Admixed American	0.43%	233
Ashkenazi Jewishnot grpmax-eligible	0.318%	315
Amishnot grpmax-eligible	0.11%	912
East Asian	0.0134%	7,479

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.Pro321=
Coding: c.963G>A
MANE Select: NM_012203
dbSNP: rs76299266
Type: single nucleotide variant
Location: chr9:37436758 (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 321: 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.Pro321Leu Benign/Likely benign ★★ ⚠ same residue
GRHPR p.Pro321Ala 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

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-pro321 (accessed [today's date]).

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