Is PKHD1 p.Ser976Pro (c.2926T>C) pathogenic?

PKHD1 p.Ser976Pro (c.2926T>C) is classified Uncertain significance in PKHD1 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-07-18). AlphaMissense: likely pathogenic (0.5933); Absent from gnomAD v4.1; Associated with autosomal recessive polycystic kidney disease.

What condition is associated with PKHD1 p.Ser976Pro (c.2926T>C)?

PKHD1 p.Ser976Pro (c.2926T>C) is associated with autosomal recessive polycystic kidney disease (ClinVar).

How common is PKHD1 p.Ser976Pro (c.2926T>C) in the general population?

PKHD1 p.Ser976Pro (c.2926T>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.Ser976Pro (c.2926T>C)?

AlphaMissense predicts likely pathogenic (score 0.5933) — an in-silico prediction, not a clinical call.

PKHD1 p.Ser976Pro

c.2926T>C · rs770882723 · VCV929019

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5933 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

autosomal recessive polycystic kidney disease

Computational evidence

Protein change
AlphaMissense	0.5933	likely pathogenic
REVEL	0.554	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	22.7	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

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.Ser976Pro
Coding: c.2926T>C
MANE Select: NM_138694
dbSNP: rs770882723
Type: single nucleotide variant
Location: chr6:52043030 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 976: a UniProt-annotated variant site (found in a patient affected by polycystic liver disease; uncertain significance); the ipt/tig 4 domain

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

Disease context

autosomal recessive polycystic kidney disease — 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.Ser976Leu Uncertain significance 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.1233+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKHD1 c.131-1G>A 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-ser976pro (accessed [today's date]).

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