Is PKHD1 p.Pro70Ser (c.208C>T) pathogenic?

PKHD1 p.Pro70Ser (c.208C>T) is classified Uncertain significance in PKHD1 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-13). AlphaMissense: likely benign (0.0796); Very rare (popmax 0.01%, amr); Associated with autosomal recessive polycystic kidney disease.

What condition is associated with PKHD1 p.Pro70Ser (c.208C>T)?

PKHD1 p.Pro70Ser (c.208C>T) is associated with autosomal recessive polycystic kidney disease (ClinVar).

How common is PKHD1 p.Pro70Ser (c.208C>T) in the general population?

PKHD1 p.Pro70Ser (c.208C>T) is very rare (popmax 0.01%, amr) (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.Pro70Ser (c.208C>T)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

PKHD1 p.Pro70Ser

c.208C>T · rs781485593 · VCV219566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

autosomal recessive polycystic kidney disease

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.288	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -2, phastCons 0.91
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	14.31	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,020 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000434% 7/1,613,974 alleles · very rare exomes 7/1,461,706 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,003
European (non-Finnish)	8.48e-05%	1,179,871

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.Pro70Ser
Coding: c.208C>T
MANE Select: NM_138694
dbSNP: rs781485593
Type: single nucleotide variant
Location: chr6:52082465 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 70: the ipt/tig 1; atypical 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.Pro70Thr Conflicting classifications of pathogenicity ★ same residue
PKHD1 p.Pro70= 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.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-pro70ser (accessed [today's date]).

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