Is GRHPR p.Leu59Phe (c.175C>T) pathogenic?

GRHPR p.Leu59Phe (c.175C>T) is classified Uncertain significance in GRHPR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-05). AlphaMissense: likely pathogenic (0.6197); Absent from gnomAD v4.1; Associated with GRHPR-related disorder.

What condition is associated with GRHPR p.Leu59Phe (c.175C>T)?

GRHPR p.Leu59Phe (c.175C>T) is associated with GRHPR-related disorder (ClinVar).

How common is GRHPR p.Leu59Phe (c.175C>T) in the general population?

GRHPR p.Leu59Phe (c.175C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRHPR p.Leu59Phe (c.175C>T)?

AlphaMissense predicts likely pathogenic (score 0.6197) — an in-silico prediction, not a clinical call.

GRHPR p.Leu59Phe

c.175C>T · VCV3344071

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6197 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GRHPR-related disorder

Computational evidence

Protein change
AlphaMissense	0.6197	likely pathogenic
REVEL	0.646	pathogenic-leaning
SaProt	LLR -11.58	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 3.9	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.0084 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GRHPR
Protein: p.Leu59Phe
Coding: c.175C>T
MANE Select: NM_012203
Type: single nucleotide variant
Location: chr9:37424936 (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

GRHPR-related disorder

Similar variants

GRHPR p.Leu59= Likely benign ★ same residue
GRHPR c.735-1G>A Pathogenic/Likely pathogenic ★★ same condition
GRHPR p.Arg124Cys Likely pathogenic ★★ same condition
GRHPR p.Arg47Ter Pathogenic/Likely pathogenic ★★ same condition
GRHPR p.Gly165Asp Pathogenic/Likely pathogenic ★★ same condition
GRHPR p.Leu59fs Likely pathogenic ★ same residue
GRHPR c.-3C>T Likely benign same condition
GRHPR c.-4G>A Likely benign 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-leu59phe (accessed [today's date]).

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