Is PKD2 p.Pro92Ser (c.274C>T) pathogenic?

PKD2 p.Pro92Ser (c.274C>T) is classified Conflicting classifications of pathogenicity in PKD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.8586); Ultra-rare (popmax 0.0405%, afr); Associated with Inborn genetic diseases.

What condition is associated with PKD2 p.Pro92Ser (c.274C>T)?

PKD2 p.Pro92Ser (c.274C>T) is associated with Inborn genetic diseases, autosomal dominant polycystic kidney disease (ClinVar).

How common is PKD2 p.Pro92Ser (c.274C>T) in the general population?

PKD2 p.Pro92Ser (c.274C>T) is ultra-rare (popmax 0.0405%, afr) (gnomAD).

What do computational predictors say about PKD2 p.Pro92Ser (c.274C>T)?

AlphaMissense predicts likely pathogenic (score 0.8586) — an in-silico prediction, not a clinical call.

PKD2 p.Pro92Ser

c.274C>T · rs940758517 · VCV2151867

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8586 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0405%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8586	likely pathogenic
REVEL	0.48	indeterminate
SaProt	LLR -8.33	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 0.83, phastCons 1
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0405% African / African-American · 29/71,532 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0251%

Overall 0.00448% 68/1,519,060 alleles · ultra-rare exomes 50/1,367,450 · genomes 18/151,610 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0405%	2,467
Middle Eastern	0.017%	5,898
Admixed American	0.0143%	7,017
Remaining individualsnot grpmax-eligible	0.00674%	14,826
European (non-Finnish)	0.00237%	42,157

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: PKD2
Protein: p.Pro92Ser
Coding: c.274C>T
MANE Select: NM_000297
dbSNP: rs940758517
Type: single nucleotide variant
Location: chr4:88008007 (GRCh38)
Structure: AlphaFold pLDDT 69.85 · 4 PDB

Full PKD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant polycystic kidney disease

Similar variants

PKD2 c.1094+1G>A Pathogenic ★★ same condition
PKD2 c.1319+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKD2 c.1548+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKD2 c.1898+5G>A Pathogenic/Likely pathogenic ★★ same condition
PKD2 c.2019+1G>A Pathogenic ★★ same condition
PKD2 c.2020-2A>G Likely pathogenic ★★ same condition
PKD2 c.2118+1G>C Pathogenic ★★ same condition
PKD2 c.2522+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/pkd2-p-pro92ser (accessed [today's date]).

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