Is PKHD1 p.Pro145Arg (c.434C>G) pathogenic?

PKHD1 p.Pro145Arg (c.434C>G) is classified Uncertain significance in PKHD1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-09-30). AlphaMissense: likely benign (0.109); Very rare (popmax 0.00774%, nfe); Associated with polycystic kidney disease 4.

What condition is associated with PKHD1 p.Pro145Arg (c.434C>G)?

PKHD1 p.Pro145Arg (c.434C>G) is associated with polycystic kidney disease 4, autosomal recessive polycystic kidney disease (ClinVar).

How common is PKHD1 p.Pro145Arg (c.434C>G) in the general population?

PKHD1 p.Pro145Arg (c.434C>G) is very rare (popmax 0.00774%, nfe) (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.Pro145Arg (c.434C>G)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

PKHD1 p.Pro145Arg

c.434C>G · rs146649894 · VCV290856

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00774%, nfe)

Conditions

polycystic kidney disease 4

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.293	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	23.9	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 0.00774% European (non-Finnish) · 91/1,176,370 alleles

Filtering AF 0.00641% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00594%

Overall 0.00571% 92/1,609,908 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00774%	12,927
African / African-American	0.00134%	74,816

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: PKHD1
Protein: p.Pro145Arg
Coding: c.434C>G
MANE Select: NM_138694
dbSNP: rs146649894
Type: single nucleotide variant
Location: chr6:52076290 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 145: the ipt/tig 2 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

Also linked: autosomal recessive polycystic kidney disease

For Autosomal recessive polycystic kidney disease (Orphanet):

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

Similar variants

PKHD1 p.Pro145= 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.11507-1G>A Likely pathogenic ★★ same condition
PKHD1 c.11665+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKHD1 c.11666-2A>G Likely pathogenic ★★ same condition
PKHD1 c.1233+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/pkhd1-p-pro145arg (accessed [today's date]).

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