Is GRHPR p.Val249Ile (c.745G>A) pathogenic?

GRHPR p.Val249Ile (c.745G>A) is classified Uncertain significance in GRHPR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-26). AlphaMissense: likely benign (0.114); Ultra-rare (popmax 0.0267%, amr); Associated with Nephrolithiasis/nephrocalcinosis.

What condition is associated with GRHPR p.Val249Ile (c.745G>A)?

GRHPR p.Val249Ile (c.745G>A) is associated with Nephrolithiasis/nephrocalcinosis, primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Val249Ile (c.745G>A) in the general population?

GRHPR p.Val249Ile (c.745G>A) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about GRHPR p.Val249Ile (c.745G>A)?

AlphaMissense predicts likely benign (score 0.114) — an in-silico prediction, not a clinical call.

GRHPR p.Val249Ile

c.745G>A · rs769568097 · VCV2469721

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.114 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Nephrolithiasis/nephrocalcinosis

Computational evidence

Protein change
AlphaMissense	0.114	likely benign
REVEL	0.406	indeterminate
SaProt	LLR -10.47	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 8.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	23.5	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 0.0267% Admixed American · 16/60,008 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00149% 24/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,751
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,088
European (non-Finnish)	0.000424%	235,989

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.Val249Ile
Coding: c.745G>A
MANE Select: NM_012203
dbSNP: rs769568097
Type: single nucleotide variant
Location: chr9:37432018 (GRCh38)
Gene constraint: LOEUF 1.313 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.80 · 4 PDB

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 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
GRHPR c.865+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-val249ile (accessed [today's date]).

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