Is PROK2 p.Ile124fs (c.370_373del) pathogenic?

PROK2 p.Ile124fs (c.370373del) is classified Likely pathogenic in PROK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-09). Associated with hypogonadotropic hypogonadism 4 with or without anosmia.

What condition is associated with PROK2 p.Ile124fs (c.370_373del)?

PROK2 p.Ile124fs (c.370_373del) is associated with hypogonadotropic hypogonadism 4 with or without anosmia (ClinVar).

PROK2 p.Ile124fs

c.370_373del · VCV3893212

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

hypogonadotropic hypogonadism 4 with or without anosmia

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 (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1

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

Variant & gene context

Gene: PROK2
Protein: p.Ile124fs
Coding: c.370_373del
MANE Select: NM_001126128
Type: Microsatellite
Location: chr3:71772741 (GRCh38)
Gene constraint: LOEUF 1.052 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 69.22

Full PROK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism 4 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROK2 p.Ser54_Ile55insTer Pathogenic ★★ same condition
PROK2 p.Gly62Asp Uncertain significance ★★ ⚠ same condition
PROK2 p.Phe99fs Uncertain significance ★★ same condition
PROK2 p.Ala28= Benign/Likely benign ★★ same condition
PROK2 p.Met1Thr Likely pathogenic ★ same condition
PROK2 c.-4C>A Conflicting classifications of pathogenicity ★ same condition
PROK2 p.Arg73Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
PROK2 p.Gly100fs Conflicting classifications of pathogenicity ★ 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/prok2-p-ile124fs (accessed [today's date]).

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