Is PKHD1 p.Arg375Pro (c.1124G>C) pathogenic?

PKHD1 p.Arg375Pro (c.1124G>C) is classified Uncertain significance in PKHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.9643); Absent from gnomAD v4.1; Associated with polycystic kidney disease 4.

What condition is associated with PKHD1 p.Arg375Pro (c.1124G>C)?

PKHD1 p.Arg375Pro (c.1124G>C) is associated with polycystic kidney disease 4 (ClinVar).

How common is PKHD1 p.Arg375Pro (c.1124G>C) in the general population?

PKHD1 p.Arg375Pro (c.1124G>C) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal recessive polycystic kidney disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PKHD1 p.Arg375Pro (c.1124G>C)?

AlphaMissense predicts likely pathogenic (score 0.9643) — an in-silico prediction, not a clinical call.

PKHD1 p.Arg375Pro

c.1124G>C · VCV3892092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9643 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

polycystic kidney disease 4

Computational evidence

Protein change
AlphaMissense	0.9643	likely pathogenic · top 1% in PKHD1
REVEL	0.717	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	24.9	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 is an independent agreement signal.

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: PKHD1
Protein: p.Arg375Pro
Coding: c.1124G>C
MANE Select: NM_138694
Type: single nucleotide variant
Location: chr6:52060037 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 375: the pa14 domain

Full PKHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

polycystic kidney disease 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive polycystic kidney disease (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Germany)

Similar variants

PKHD1 p.Arg375Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
PKHD1 p.Arg375Gln Uncertain significance ★ same residue
PKHD1 p.Arg375= Likely benign ★ same residue
PKHD1 c.11174+2T>C Likely pathogenic ★★ same condition
PKHD1 c.11310+1G>C Pathogenic/Likely pathogenic ★★ same condition
PKHD1 c.11398+2T>C Pathogenic/Likely pathogenic ★★ same condition
PKHD1 c.11665+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKHD1 c.11666-2A>G 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/pkhd1-p-arg375pro (accessed [today's date]).

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