Is GRHPR p.Leu282Phe (c.844C>T) pathogenic?

GRHPR p.Leu282Phe (c.844C>T) is classified Likely benign in GRHPR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: ambiguous (0.5206); Ultra-rare (popmax 0.0831%, nfe); Associated with primary hyperoxaluria type 2.

What condition is associated with GRHPR p.Leu282Phe (c.844C>T)?

GRHPR p.Leu282Phe (c.844C>T) is associated with primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Leu282Phe (c.844C>T) in the general population?

GRHPR p.Leu282Phe (c.844C>T) is ultra-rare (popmax 0.0831%, 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.Leu282Phe (c.844C>T)?

AlphaMissense predicts ambiguous (score 0.5206) — an in-silico prediction, not a clinical call.

GRHPR p.Leu282Phe

c.844C>T · rs202120724 · VCV1091045

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5206 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0831%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

primary hyperoxaluria type 2

Computational evidence

Protein change
AlphaMissense	0.5206	ambiguous
REVEL	0.79	moderately pathogenic-leaning
SaProt	LLR -10.73	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	28.4	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 0.0831% European (non-Finnish) · 981/1,179,936 alleles

Filtering AF 0.0788% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0771%

Overall 0.0636% 1,027/1,613,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0831%	1,203
Remaining individualsnot grpmax-eligible	0.0352%	2,840
Admixed American	0.025%	4,000
African / African-American	0.0107%	9,366
Finnishnot grpmax-eligible	0.00156%	64,042

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.Leu282Phe
Coding: c.844C>T
MANE Select: NM_012203
dbSNP: rs202120724
Type: single nucleotide variant
Location: chr9:37432117 (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 282: 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.Leu282= Likely benign ★ same residue
GRHPR p.Leu282Pro Uncertain significance ⚠ same residue
GRHPR p.Leu282_Leu283insTer 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

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-leu282phe (accessed [today's date]).

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