Is PKHD1 p.Ser522Phe (c.1565C>T) pathogenic?

PKHD1 p.Ser522Phe (c.1565C>T) is classified Uncertain significance in PKHD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-10). AlphaMissense: likely benign (0.1697); Ultra-rare (popmax 0.018%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PKHD1 p.Ser522Phe (c.1565C>T)?

PKHD1 p.Ser522Phe (c.1565C>T) is associated with Inborn genetic diseases, polycystic kidney disease 4 (ClinVar).

How common is PKHD1 p.Ser522Phe (c.1565C>T) in the general population?

PKHD1 p.Ser522Phe (c.1565C>T) is ultra-rare (popmax 0.018%, nfe) (gnomAD).

What do computational predictors say about PKHD1 p.Ser522Phe (c.1565C>T)?

AlphaMissense predicts likely benign (score 0.1697) — an in-silico prediction, not a clinical call.

PKHD1 p.Ser522Phe

c.1565C>T · rs746561147 · VCV592200

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1697 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1697	likely benign
REVEL	0.331	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	21.7	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

Grpmax group 0.018% European (non-Finnish) · 212/1,179,900 alleles

Filtering AF 0.016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0138% 222/1,613,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.018%	5,566
Remaining individualsnot grpmax-eligible	0.0128%	7,809
African / African-American	0.00267%	37,455

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.Ser522Phe
Coding: c.1565C>T
MANE Select: NM_138694
dbSNP: rs746561147
Type: single nucleotide variant
Location: chr6:52056927 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 522: a UniProt-annotated variant site (found in a patient affected by polycystic liver disease; uncertain significance)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: polycystic kidney disease 4

Similar variants

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
PKHD1 c.131-1G>A Likely pathogenic ★★ same condition
PKHD1 c.1513-1G>A Pathogenic/Likely pathogenic ★★ same condition
PKHD1 c.1602+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-ser522phe (accessed [today's date]).

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