Is GRHPR p.Val248Ile (c.742G>A) pathogenic?

GRHPR p.Val248Ile (c.742G>A) is classified Conflicting classifications of pathogenicity in GRHPR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-10-27). AlphaMissense: likely benign (0.103); Ultra-rare (popmax 0.0233%, amr); Associated with primary hyperoxaluria type 2.

What condition is associated with GRHPR p.Val248Ile (c.742G>A)?

GRHPR p.Val248Ile (c.742G>A) is associated with primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Val248Ile (c.742G>A) in the general population?

GRHPR p.Val248Ile (c.742G>A) is ultra-rare (popmax 0.0233%, amr) (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.Val248Ile (c.742G>A)?

AlphaMissense predicts likely benign (score 0.103) — an in-silico prediction, not a clinical call.

GRHPR p.Val248Ile

c.742G>A · rs369950120 · VCV969060

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.103 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

primary hyperoxaluria type 2

Computational evidence

Protein change
AlphaMissense	0.103	likely benign
REVEL	0.315	indeterminate
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	21.6	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 0.0233% Admixed American · 14/60,012 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.007% 113/1,613,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,287
African / African-American	0.012%	8,324
European (non-Finnish)	0.00703%	14,216
Remaining individualsnot grpmax-eligible	0.0064%	15,622
East Asian	0.00223%	44,902
South Asian	0.0022%	45,541

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.Val248Ile
Coding: c.742G>A
MANE Select: NM_012203
dbSNP: rs369950120
Type: single nucleotide variant
Location: chr9:37432015 (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.Val248Asp 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-val248ile (accessed [today's date]).

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