Is PKHD1 p.Arg1422Pro (c.4265G>C) pathogenic?

PKHD1 p.Arg1422Pro (c.4265G>C) is classified Uncertain significance in PKHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-19). AlphaMissense: ambiguous (0.3422); Absent from gnomAD v4.1.

How common is PKHD1 p.Arg1422Pro (c.4265G>C) in the general population?

PKHD1 p.Arg1422Pro (c.4265G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PKHD1 p.Arg1422Pro (c.4265G>C)?

AlphaMissense predicts ambiguous (score 0.3422) — an in-silico prediction, not a clinical call.

PKHD1 p.Arg1422Pro

c.4265G>C · rs557773345 · VCV285782

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3422 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.3422	ambiguous
REVEL	0.309	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP -2.6, phastCons 0.36
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	11.88	PHRED · no single calibrated threshold — expert panels disagree

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.Arg1422Pro
Coding: c.4265G>C
MANE Select: NM_138694
dbSNP: rs557773345
Type: single nucleotide variant
Location: chr6:52025545 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 1422: a UniProt-annotated variant site (found in a patient affected by polycystic liver disease; uncertain significance); the ipt/tig 9 domain

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

Similar variants

PKHD1 p.Arg1422Gln Uncertain significance ★★ ⚠ same residue
PKHD1 p.Arg1422= Conflicting classifications of pathogenicity ★ same residue
PKHD1 p.Arg1422Trp Uncertain significance ★ same residue
PKHD1 c.11174+2T>C Likely pathogenic ★★ same type
PKHD1 c.11310+1G>C Pathogenic/Likely pathogenic ★★ same type
PKHD1 c.11398+2T>C Pathogenic/Likely pathogenic ★★ same type
PKHD1 c.11507-1G>A Likely pathogenic ★★ same type
PKHD1 c.11665+1G>A Pathogenic/Likely pathogenic ★★ same type

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-arg1422pro (accessed [today's date]).

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