Is PKHD1 p.Ala17Ser (c.49G>T) pathogenic?

PKHD1 p.Ala17Ser (c.49G>T) is classified Uncertain significance in PKHD1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-17). AlphaMissense: likely benign (0.1001); Ultra-rare (popmax 0.0121%, afr); Associated with polycystic kidney disease 4.

What condition is associated with PKHD1 p.Ala17Ser (c.49G>T)?

PKHD1 p.Ala17Ser (c.49G>T) is associated with polycystic kidney disease 4, autosomal recessive polycystic kidney disease (ClinVar).

How common is PKHD1 p.Ala17Ser (c.49G>T) in the general population?

PKHD1 p.Ala17Ser (c.49G>T) is ultra-rare (popmax 0.0121%, afr) (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.Ala17Ser (c.49G>T)?

AlphaMissense predicts likely benign (score 0.1001) — an in-silico prediction, not a clinical call.

PKHD1 p.Ala17Ser

c.49G>T · rs149293970 · VCV909295

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1001 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

polycystic kidney disease 4

Computational evidence

Protein change
AlphaMissense	0.1001	likely benign
REVEL	0.089	moderately 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 0.63	GERP -2.5, phastCons 0.43
Regional constraint	o/e 0.97	unconstrained · MANE · 466 kb · p 0.074 · regional, not allelic
Overall
CADD	9.536	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 0.0121% African / African-American · 9/74,624 alleles

Filtering AF 0.00626% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00469%

Overall 0.000564% 9/1,596,028 alleles · ultra-rare exomes 1/1,443,794 · genomes 8/152,234 · joint denominator

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.Ala17Ser
Coding: c.49G>T
MANE Select: NM_138694
dbSNP: rs149293970
Type: single nucleotide variant
Location: chr6:52084885 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Residue 17: a UniProt-annotated variant site (in pkd4)

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

Also linked: autosomal recessive polycystic kidney disease

For Autosomal recessive polycystic kidney disease (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Germany)

Similar variants

PKHD1 p.Ala17Val Uncertain significance ★★ same residue
PKHD1 p.Ala17= Conflicting classifications of pathogenicity ★ same residue
PKHD1 p.Ala17Thr 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

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-ala17ser (accessed [today's date]).

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