Is PKHD1 p.Ser2136Arg (c.6408C>A) pathogenic?

PKHD1 p.Ser2136Arg (c.6408C>A) is classified Uncertain significance in PKHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: likely pathogenic (0.8023); Rare (popmax 0.111%, sas); Associated with polycystic kidney disease 4.

What condition is associated with PKHD1 p.Ser2136Arg (c.6408C>A)?

PKHD1 p.Ser2136Arg (c.6408C>A) is associated with polycystic kidney disease 4 (ClinVar).

How common is PKHD1 p.Ser2136Arg (c.6408C>A) in the general population?

PKHD1 p.Ser2136Arg (c.6408C>A) is rare (popmax 0.111%, sas) (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.Ser2136Arg (c.6408C>A)?

AlphaMissense predicts likely pathogenic (score 0.8023) — an in-silico prediction, not a clinical call.

PKHD1 p.Ser2136Arg

c.6408C>A · VCV3593864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8023 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.111%, sas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

polycystic kidney disease 4

Computational evidence

Protein change
AlphaMissense	0.8023	likely pathogenic · top 5% in PKHD1
REVEL	0.733	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	22.1	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.111% South Asian · 101/91,032 alleles

Filtering AF 0.0933% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0869%

Overall 0.00695% 112/1,610,986 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.111%	901
Remaining individualsnot grpmax-eligible	0.0128%	7,798
East Asian	0.00669%	14,951

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.Ser2136Arg
Coding: c.6408C>A
MANE Select: NM_138694
Type: single nucleotide variant
Location: chr6:51911881 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 2136: 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

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.Ser2136Gly 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.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

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-ser2136arg (accessed [today's date]).

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