Is PKD1 p.Pro6Ser (c.16C>T) pathogenic?

PKD1 p.Pro6Ser (c.16C>T) is classified Uncertain significance in PKD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-03-08). AlphaMissense: likely benign (0.2231); Ultra-rare (popmax 0.0257%, amr); Associated with PKD1-related disorder.

What condition is associated with PKD1 p.Pro6Ser (c.16C>T)?

PKD1 p.Pro6Ser (c.16C>T) is associated with PKD1-related disorder, polycystic kidney disease 1 (ClinVar).

How common is PKD1 p.Pro6Ser (c.16C>T) in the general population?

PKD1 p.Pro6Ser (c.16C>T) is ultra-rare (popmax 0.0257%, amr) (gnomAD).

What do computational predictors say about PKD1 p.Pro6Ser (c.16C>T)?

AlphaMissense predicts likely benign (score 0.2231) — an in-silico prediction, not a clinical call.

PKD1 p.Pro6Ser

c.16C>T · rs1320256969 · VCV1312334

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2231 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0257%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

PKD1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2231	likely benign
REVEL	0.066	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 6.1	GERP 1, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 174 bp · p 0.011 · regional, not allelic
Overall
CADD	23.8	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 0.0257% Admixed American · 4/15,562 alleles

Filtering AF 0.00877% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00521%

Overall 0.000525% 4/762,212 alleles · ultra-rare exomes 0/615,932 · genomes 4/146,280 · 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: PKD1
Protein: p.Pro6Ser
Coding: c.16C>T
MANE Select: NM_001009944
dbSNP: rs1320256969
Type: single nucleotide variant
Location: chr16:2135674 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

Full PKD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PKD1-related disorder

Also linked: polycystic kidney disease 1

Similar variants

PKD1 p.Pro6Arg Uncertain significance ★ ⚠ same residue
PKD1 p.Pro6fs Pathogenic ★★ same residue
PKD1 c.10619-2A>G Pathogenic ★★ same condition
PKD1 c.10821+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.10821+2T>G Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.11017-10C>A Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.11017-25A>C Likely pathogenic ★★ same condition
PKD1 c.11017-25A>G 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/pkd1-p-pro6ser (accessed [today's date]).

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