Is GRHPR p.Pro203fs (c.608_609del) pathogenic?

GRHPR p.Pro203fs (c.608609del) is classified Pathogenic/Likely pathogenic in GRHPR (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-01-27). Very rare (popmax 0.00223%, eas); Associated with primary hyperoxaluria type 2.

What condition is associated with GRHPR p.Pro203fs (c.608_609del)?

GRHPR p.Pro203fs (c.608_609del) is associated with primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Pro203fs (c.608_609del) in the general population?

GRHPR p.Pro203fs (c.608_609del) 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.

GRHPR p.Pro203fs

c.608_609del · rs180177316 · VCV204252

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

primary hyperoxaluria type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.9	GERP -3.7
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,898 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000744% 12/1,613,538 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,898
African / African-American	0.00133%	74,912
European (non-Finnish)	0.000848%	117,954

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.Pro203fs
Coding: c.608_609del
MANE Select: NM_012203
dbSNP: rs180177316
Type: Deletion
Location: chr9:37430520 (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 203: 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 c.206_214+11del Likely pathogenic ★★ same condition
GRHPR c.735-2del Likely pathogenic ★★ same condition
GRHPR p.Ala197fs Pathogenic/Likely pathogenic ★★ same condition
GRHPR p.Ala206fs Pathogenic/Likely pathogenic ★★ same condition
GRHPR p.Ala52fs Pathogenic/Likely pathogenic ★★ same condition
GRHPR p.Asp35fs Pathogenic ★★ same condition
GRHPR p.Asp91fs Pathogenic/Likely pathogenic ★★ same condition
GRHPR p.Gln232fs 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-pro203fs (accessed [today's date]).

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