Is GRHPR p.Gly319Trp (c.955G>T) pathogenic?

GRHPR p.Gly319Trp (c.955G>T) is classified Conflicting classifications of pathogenicity in GRHPR (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.6628); Ultra-rare (popmax 0.0382%, nfe); Associated with primary hyperoxaluria type 2.

What condition is associated with GRHPR p.Gly319Trp (c.955G>T)?

GRHPR p.Gly319Trp (c.955G>T) is associated with primary hyperoxaluria type 2 (ClinVar).

How common is GRHPR p.Gly319Trp (c.955G>T) in the general population?

GRHPR p.Gly319Trp (c.955G>T) is ultra-rare (popmax 0.0382%, nfe) (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.Gly319Trp (c.955G>T)?

AlphaMissense predicts likely pathogenic (score 0.6628) — an in-silico prediction, not a clinical call.

GRHPR p.Gly319Trp

c.955G>T · rs142835989 · VCV427140

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.6628 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0382%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary hyperoxaluria type 2

Computational evidence

Protein change
AlphaMissense	0.6628	likely pathogenic
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -16.21	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	33.0	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 0.0382% European (non-Finnish) · 451/1,179,998 alleles

Filtering AF 0.0353% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0341%

Overall 0.0302% 487/1,613,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.329%	304
European (non-Finnish)grpmax	0.0382%	2,616
Remaining individualsnot grpmax-eligible	0.0304%	3,289
Admixed American	0.0133%	7,498
African / African-American	0.00667%	14,983
East Asian	0.00223%	44,888

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gly319Trp
Coding: c.955G>T
MANE Select: NM_012203
dbSNP: rs142835989
Type: single nucleotide variant
Location: chr9:37436750 (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

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.Gly319Arg Uncertain significance ★ ⚠ same residue
GRHPR p.Gly319= 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-gly319trp (accessed [today's date]).

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