Is GRHPR p.Pro321Leu (c.962C>T) pathogenic?

GRHPR p.Pro321Leu (c.962C>T) is classified Benign/Likely benign in GRHPR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.1144); Low-frequency (popmax 1.48%, afr); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with GRHPR p.Pro321Leu (c.962C>T)?

GRHPR p.Pro321Leu (c.962C>T) is associated with Nephrolithiasis/nephrocalcinosis, primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Pro321Leu (c.962C>T) in the general population?

GRHPR p.Pro321Leu (c.962C>T) is low-frequency (popmax 1.48%, afr) (gnomAD).

What do computational predictors say about GRHPR p.Pro321Leu (c.962C>T)?

AlphaMissense predicts likely benign (score 0.1144) — an in-silico prediction, not a clinical call.

GRHPR p.Pro321Leu

c.962C>T · rs142356700 · VCV366861

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1144 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.48%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.1144	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -10.09	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 2, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	24.1	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 1.48% African / African-American · 1,111/75,004 alleles

Filtering AF 1.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.38%

Overall 0.0853% 1,376/1,614,048 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.48%	68
Remaining individualsnot grpmax-eligible	0.144%	695
Admixed American	0.103%	968
Middle Eastern	0.0495%	2,021
European (non-Finnish)	0.00881%	11,346
South Asian	0.00549%	18,215
East Asian	0.00223%	44,876

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.Pro321Leu
Coding: c.962C>T
MANE Select: NM_012203
dbSNP: rs142356700
Type: single nucleotide variant
Location: chr9:37436757 (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

Nephrolithiasis/nephrocalcinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: primary hyperoxaluria type 2

Similar variants

GRHPR p.Pro321= 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-pro321leu (accessed [today's date]).

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