# NM_000444.6(PHEX):c.2092_2096del (p.Pro698fs)

https://sugi.bio/variant/phex-p-pro698fs

## Summary

**PHEX p.Pro698fs (c.2092_2096del)** is classified **Pathogenic** in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). No gnomAD frequency available for this variant; Associated with X-linked dominant hypophosphatemic rickets.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2147213985 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PHEX gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to X-linked dominant hypophosphatemic rickets.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked dominant |
| Age of onset (of this condition) | Childhood, Infancy |
| Prevalence | 1-9 / 100 000 (Norway) |
| Clinical trials | 45 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PHEX is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of X-linked hypophosphatemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal phosphate wasting — Very frequent (99-80%)
- Hypophosphatemia — Very frequent (99-80%)
- Rickets — Very frequent (99-80%)
- Hypocalciuria — Very frequent (99-80%)
- Elevated circulating alkaline phosphatase concentration — Very frequent (99-80%)
- Abnormality of lower-limb metaphyses — Very frequent (99-80%)
- Nephrocalcinosis — Frequent (79-30%)
- Odontodysplasia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012943/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PHEX](https://sugi.bio/atlas/gene/PHEX/) |
| Protein change (HGVS p.) | p.Pro698fs |
| Coding change (HGVS c.) | c.2092_2096del |
| MANE Select transcript | [NM_000444](https://www.ncbi.nlm.nih.gov/nuccore/NM_000444) |
| dbSNP | [rs2147213985](https://www.ncbi.nlm.nih.gov/snp/rs2147213985/) |
| Variant type | Deletion |
| Location | chrX:22245350-22245354 (GRCh38) |
| ClinVar | [VCV1686053](https://www.ncbi.nlm.nih.gov/clinvar/variation/1686053/) |

**All HGVS expressions:** `NC_000023.10:g.22263471_22263475del`, `NC_000023.11:g.22245354_22245358del`, `NG_007563.2:g.217551_217555del`, `NM_000444.6:c.2092_2096del`, `NM_001282754.2:c.2071-2497_2071-2493del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.206, GERP 2.53, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 21 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PHEX** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **X-linked dominant hypophosphatemic rickets** — Definitive (XL)

## Protein context {#protein}

Residue **698** lies in the peptidase m13 domain.

AlphaFold model confidence (whole protein): pLDDT 94.58, 90% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-04.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |

## Associated conditions {#conditions}

[X-linked dominant hypophosphatemic rickets](https://sugi.bio/atlas/disease/x-linked-dominant-hypophosphatemic-rickets/).

**Reported phenotype names (ClinVar):** Familial X-linked hypophosphatemic vitamin D refractory rickets, Hypophosphatemic Rickets, X-Linked Dominant, X-Linked Hypophosphatemia, HYPOPHOSPHATEMIC VITAMIN D-RESISTANT RICKETS, Hypophosphatemia, vitamin D-resistant rickets, Vitamin D-resistant rickets,  X-linked.

## Similar variants {#similar}

Related PHEX variant pages (same residue, condition, or type): [PHEX c.1079+2_1079+5del](/variant/phex-c-1079-plus-2-1079-plus-5del), [PHEX c.187+1del](/variant/phex-c-187-plus-1del), [PHEX p.Ala242fs](/variant/phex-p-ala242fs), [PHEX p.Ala730fs](/variant/phex-p-ala730fs), [PHEX p.Leu438fs](/variant/phex-p-leu438fs), [PHEX p.Phe731fs](/variant/phex-p-phe731fs), [PHEX p.Trp520fs](/variant/phex-p-trp520fs), [PHEX p.Pro698Ser](/variant/phex-p-pro698ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 1686053). 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.*