Is PKDCC p.Pro77fs (c.228dup) pathogenic?

PKDCC p.Pro77fs (c.228dup) is classified Likely pathogenic in PKDCC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-28). Very rare (popmax 0.00379%, sas); Associated with rhizomelic limb shortening with dysmorphic features.

What condition is associated with PKDCC p.Pro77fs (c.228dup)?

PKDCC p.Pro77fs (c.228dup) is associated with rhizomelic limb shortening with dysmorphic features (ClinVar).

How common is PKDCC p.Pro77fs (c.228dup) in the general population?

PKDCC p.Pro77fs (c.228dup) is very rare (popmax 0.00379%, sas) (gnomAD).

PKDCC p.Pro77fs

c.228dup · rs2465740345 · VCV1803946

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00379%, sas)

Conditions

rhizomelic limb shortening with dysmorphic features

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 7
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.8	GERP -0.62
Region caveats
Repeat context	tandem	G-rich low complexity · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00379% South Asian · 1/26,376 alleles

Overall 8.95e-05% 1/1,117,352 alleles · very rare exomes 1/973,354 · genomes 0/143,998 · 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.Pro77fs
Coding: c.228dup
MANE Select: NM_138370
dbSNP: rs2465740345
Type: Duplication
Location: chr2:42048424 (GRCh38)
Gene constraint: LOEUF 1.15 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.96
Residue 77: the 'disordered' region

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

Disease context

rhizomelic limb shortening with dysmorphic features — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PKDCC p.Leu314fs Pathogenic ★ same condition
PKDCC p.Pro77= Likely benign ★ same residue
PKDCC p.Leu262Arg Pathogenic/Likely pathogenic ★★ same condition
PKDCC p.Ser109Pro Benign ★★ same condition
PKDCC c.640-2A>T Likely pathogenic ★ same condition
PKDCC p.Arg252Ter Pathogenic ★ same condition
PKDCC p.Leu97fs Likely pathogenic ★ same condition
PKDCC p.Trp376Ter 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/pkdcc-p-pro77fs (accessed [today's date]).

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