Is PKDCC p.Cys331Arg (c.991T>C) pathogenic?

PKDCC p.Cys331Arg (c.991T>C) is classified Uncertain significance in PKDCC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.997); Very rare (popmax 0.00034%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PKDCC p.Cys331Arg (c.991T>C)?

PKDCC p.Cys331Arg (c.991T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PKDCC p.Cys331Arg (c.991T>C) in the general population?

PKDCC p.Cys331Arg (c.991T>C) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about PKDCC p.Cys331Arg (c.991T>C)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

PKDCC p.Cys331Arg

c.991T>C · rs757512363 · VCV1478856

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic · top 3% in PKDCC
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -15.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,485 bp · p 0.012 · regional, not allelic
Overall
CADD	29.4	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 0.00034% European (non-Finnish) · 4/1,175,962 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,605,872 alleles · very rare exomes 3/1,453,706 · genomes 1/152,166 · 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: PKDCC
Protein: p.Cys331Arg
Coding: c.991T>C
MANE Select: NM_138370
dbSNP: rs757512363
Type: single nucleotide variant
Location: chr2:42054264 (GRCh38)
Gene constraint: LOEUF 1.15 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.96
Residue 331: a UniProt-annotated variant site (in rlsdf); the protein kinase domain

Full PKDCC 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

Similar variants

PKDCC p.Cys331= Likely benign ★ same residue
PKDCC p.Ala299Thr Uncertain significance ★★ ⚠ same condition
PKDCC p.Arg280Cys Uncertain significance ★★ ⚠ same condition
PKDCC p.Arg338Gln Uncertain significance ★★ ⚠ same condition
PKDCC p.Arg393Gln Uncertain significance ★★ ⚠ same condition
PKDCC p.Asp295Glu Uncertain significance ★★ ⚠ same condition
PKDCC p.Asp89His Uncertain significance ★★ ⚠ same condition
PKDCC p.Glu380Lys Uncertain significance ★★ ⚠ 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/pkdcc-p-cys331arg (accessed [today's date]).

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