Is PROK2 p.Phe99fs (c.297del) pathogenic?

PROK2 p.Phe99fs (c.297del) is classified Uncertain significance in PROK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.016%, afr); Associated with PROK2-related disorder.

What condition is associated with PROK2 p.Phe99fs (c.297del)?

PROK2 p.Phe99fs (c.297del) is associated with PROK2-related disorder, hypogonadotropic hypogonadism 4 with or without anosmia (ClinVar).

How common is PROK2 p.Phe99fs (c.297del) in the general population?

PROK2 p.Phe99fs (c.297del) is ultra-rare (popmax 0.016%, afr) (gnomAD).

PROK2 p.Phe99fs

c.297del · rs768413190 · VCV2309812

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Conditions

PROK2-related disorder

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 7.7	GERP 2.4, phastCons 1
Overall
CADD	15.42	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 0.016% African / African-American · 12/74,876 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000806% 13/1,613,858 alleles · ultra-rare exomes 8/1,461,798 · genomes 5/152,060 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,240
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: PROK2
Protein: p.Phe99fs
Coding: c.297del
MANE Select: NM_001126128
dbSNP: rs768413190
Type: Deletion
Location: chr3:71772817 (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

PROK2-related disorder

Also linked: hypogonadotropic hypogonadism 4 with or without anosmia

Similar variants

PROK2 p.Phe99Ser Likely benign same residue
PROK2 p.Ser54_Ile55insTer Pathogenic ★★ same condition
PROK2 p.Thr21fs Likely pathogenic same condition
PROK2 p.Gly62Asp Uncertain significance ★★ ⚠ same condition
PROK2 p.Ala28= Benign/Likely benign ★★ same condition
PROK2 p.Ile124fs Likely pathogenic ★ same condition
PROK2 p.Met1Thr Likely pathogenic ★ same condition
PROK2 c.-4C>A 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-phe99fs (accessed [today's date]).

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