Is GRHPR p.Ala112= (c.336C>T) pathogenic?

GRHPR p.Ala112= (c.336C>T) is classified Conflicting classifications of pathogenicity in GRHPR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-04). Ultra-rare (popmax 0.0249%, nfe); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with GRHPR p.Ala112= (c.336C>T)?

GRHPR p.Ala112= (c.336C>T) is associated with Nephrolithiasis/nephrocalcinosis, primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Ala112= (c.336C>T) in the general population?

GRHPR p.Ala112= (c.336C>T) is ultra-rare (popmax 0.0249%, nfe) (gnomAD).

GRHPR p.Ala112=

c.336C>T · rs148778319 · VCV366854

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0249%, nfe)

Conditions

Nephrolithiasis/nephrocalcinosis

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 -9.3	GERP -3.9
Overall
CADD	0.975	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0249% European (non-Finnish) · 294/1,179,902 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.0196% 316/1,614,040 alleles · ultra-rare exomes 295/1,461,724 · genomes 21/152,316 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0249%	4,013
Middle Eastern	0.0165%	6,062
African / African-American	0.0133%	7,504
Remaining individualsnot grpmax-eligible	0.008%	12,501
Admixed American	0.00333%	30,015
South Asian	0.00329%	30,359
East Asian	0.00223%	44,884

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.Ala112=
Coding: c.336C>T
MANE Select: NM_012203
dbSNP: rs148778319
Type: single nucleotide variant
Location: chr9:37426586 (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 112: 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.Ala112Thr 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
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-ala112 (accessed [today's date]).

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