# NM_144773.4(PROKR2):c.868C>T (p.Pro290Ser)

https://sugi.bio/variant/prokr2-p-pro290ser

## Summary

**PROKR2 p.Pro290Ser (c.868C>T)** is classified **Conflicting classifications of pathogenicity** in PROKR2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.8993); Ultra-rare (popmax 0.035%, amr); Associated with Male infertility with spermatogenesis disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs149992595 · 10 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.035%, amr)

## For patients & families {#patients}

This is a change in the PROKR2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 10 submitters, and is linked to Male infertility with spermatogenesis disorder.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PROKR2](https://sugi.bio/atlas/gene/PROKR2/) |
| Protein change (HGVS p.) | p.Pro290Ser |
| Coding change (HGVS c.) | c.868C>T |
| MANE Select transcript | [NM_144773](https://www.ncbi.nlm.nih.gov/nuccore/NM_144773) |
| dbSNP | [rs149992595](https://www.ncbi.nlm.nih.gov/snp/rs149992595/) |
| Variant type | single nucleotide variant |
| Location | chr20:5302327-5302327 (GRCh38) |
| ClinVar | [VCV897086](https://www.ncbi.nlm.nih.gov/clinvar/variation/897086/) |

**All HGVS expressions:** `NC_000020.10:g.5282973G>A`, `NC_000020.11:g.5302327G>A`, `NG_008132.2:g.17043C>T`, `NM_144773.4:c.868C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.8993)
- REVEL 0.939 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.757 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.806, GERP 1.86, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 30.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.89** across the covering region of the MANE Select transcript (5,302,043–5,314,369), spanning 12,326 bp. Chi-square p 0.0097. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.035%** (amr) · FAF95 0.0259% · FAF99 0.025% · 21/60,028 in the highest group · 382/1,614,204 alleles overall — ultra-rare (popmax 0.035%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.035% | 2,858 |
| Middle Eastern | 0.033% | 3,031 |
| Remaining individuals (not grpmax-eligible) | 0.0304% | 3,290 |
| European (non-Finnish) | 0.0285% | 3,512 |
| African / African-American | 0.00533% | 18,762 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PROKR2** population constraint: LOEUF 1.492, pLI 4.2632e-10, missense-Z 1.3401. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hypogonadotropic hypogonadism 3 with or without anosmia** — Definitive (AD)

## Protein context {#protein}

Residue **290** lies in a UniProt-annotated variant site (in hh3; phenotype consistent with kallmann syndrome; signaling activity is impaired; impaired cell surface-targeting).

AlphaFold model confidence (whole protein): pLDDT 78.50, 50% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of PROKR2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

PROKR2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-06.

**Submitter consensus:** conflicting (5 Uncertain significance, 3 Likely pathogenic, 2 Pathogenic).

**Submission history:** 10 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-28 |
| Genomics England Pilot Project, Genomics England | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-06-19 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-09 |
| Laan Lab, Human Genetics Research Group, University of Tartu | Likely pathogenic | criteria provided, single submitter | research | 2023-09-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-16 |
| NHS Central & South Genomic Laboratory Hub | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-06 |
| Laboratoire de Génétique Moléculaire, CHU Bordeaux | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-05 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-22 |

## Associated conditions {#conditions}

[Male infertility with spermatogenesis disorder](https://sugi.bio/atlas/disease/male-infertility-with-spermatogenesis-disorder/), [hypogonadotropic hypogonadism 3 with or without anosmia](https://sugi.bio/atlas/disease/hypogonadotropic-hypogonadism-3-with-or-without-anosmia/), [hypogonadotropic hypogonadism](https://sugi.bio/atlas/disease/hypogonadotropic-hypogonadism/).

**Reported phenotype names (ClinVar):** Male infertility with spermatogenesis disorder, Hypogonadotropic hypogonadism 3 with or without anosmia, not provided, Hypogonadotropic hypogonadism, none provided, Hypogonadotropic hypogonadism with or without anosmia, Hypogonadotrophic hypogonadism, Isolated hypogonadotropic hypogonadism, Low gonadotropins (secondary hypogonadism), HYPOGONADOTROPIC HYPOGONADISM 3 WITH ANOSMIA.

## Similar variants {#similar}

Related PROKR2 variant pages (same residue, condition, or type): [PROKR2 p.Pro290=](/variant/prokr2-p-pro290), [PROKR2 p.Arg164Gln](/variant/prokr2-p-arg164gln), [PROKR2 p.Glu231Lys](/variant/prokr2-p-glu231lys), [PROKR2 p.Tyr316Ter](/variant/prokr2-p-tyr316ter), [PROKR2 p.Ala103Val](/variant/prokr2-p-ala103val), [PROKR2 p.Ala129Thr](/variant/prokr2-p-ala129thr), [PROKR2 p.Ala156Thr](/variant/prokr2-p-ala156thr), [PROKR2 p.Arg135Cys](/variant/prokr2-p-arg135cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 897086). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*