Is PROKR2 p.Pro256fs (c.767del) pathogenic?

PROKR2 p.Pro256fs (c.767del) is classified Uncertain significance in PROKR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-06). Very rare (popmax 0.000424%, nfe).

How common is PROKR2 p.Pro256fs (c.767del) in the general population?

PROKR2 p.Pro256fs (c.767del) is very rare (popmax 0.000424%, nfe) (gnomAD).

PROKR2 p.Pro256fs

c.767del · VCV3339711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -7.1	GERP -3.7
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,038 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,100 alleles · very rare

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: PROKR2
Protein: p.Pro256fs
Coding: c.767del
MANE Select: NM_144773
Type: Deletion
Location: chr20:5302428 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50

Full PROKR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PROKR2 p.His20fs Pathogenic/Likely pathogenic ★★ same type
PROKR2 p.Glu377_Val378del Uncertain significance ★★ same type
PROKR2 p.Asp34fs Pathogenic ★ same type
PROKR2 p.Phe109fs Likely pathogenic ★ same type
PROKR2 p.Val131fs Pathogenic ★ same type

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/prokr2-p-pro256fs (accessed [today's date]).

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