Is GRHPR p.Val248Asp (c.743T>A) pathogenic?

GRHPR p.Val248Asp (c.743T>A) is classified Conflicting classifications of pathogenicity in GRHPR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-03). AlphaMissense: likely pathogenic (0.9657); Very rare (popmax 0.00223%, eas); Associated with primary hyperoxaluria type 2.

What condition is associated with GRHPR p.Val248Asp (c.743T>A)?

GRHPR p.Val248Asp (c.743T>A) is associated with primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Val248Asp (c.743T>A) in the general population?

GRHPR p.Val248Asp (c.743T>A) is very rare (popmax 0.00223%, eas) (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.Val248Asp (c.743T>A)?

AlphaMissense predicts likely pathogenic (score 0.9657) — an in-silico prediction, not a clinical call.

GRHPR p.Val248Asp

c.743T>A · rs796052079 · VCV204236

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary hyperoxaluria type 2

Computational evidence

Protein change
AlphaMissense	0.9657	likely pathogenic · top 6% in GRHPR
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -14.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	25.9	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 0.00223% East Asian · 1/44,896 alleles

Overall 0.000186% 3/1,613,982 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
Admixed American	0.00167%	60,010
European (non-Finnish)	8.47e-05%	1,179,970

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.Val248Asp
Coding: c.743T>A
MANE Select: NM_012203
dbSNP: rs796052079
Type: single nucleotide variant
Location: chr9:37432016 (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 248: 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.Val248Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
GRHPR p.Val248= Likely benign ★★ 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-val248asp (accessed [today's date]).

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