# NM_000444.6(PHEX):c.1166del (p.Phe389fs)

https://sugi.bio/variant/phex-p-phe389fs

## Summary

**PHEX p.Phe389fs (c.1166del)** is classified **Pathogenic** in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). Associated with PHEX-related disorder.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## 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 PHEX-related 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 | [PHEX](https://sugi.bio/atlas/gene/PHEX/) |
| Protein change (HGVS p.) | p.Phe389fs |
| Coding change (HGVS c.) | c.1166del |
| MANE Select transcript | [NM_000444](https://www.ncbi.nlm.nih.gov/nuccore/NM_000444) |
| Variant type | Deletion |
| Location | chrX:22111552-22111552 (GRCh38) |
| ClinVar | [VCV4949322](https://www.ncbi.nlm.nih.gov/clinvar/variation/4949322/) |

**All HGVS expressions:** `NC_000023.10:g.22129671del`, `NC_000023.11:g.22111553del`, `NG_007563.2:g.83751del`, `NG_007563.3:g.84230del`, `NM_000444.6:c.1166del`, `NM_001282754.2:c.1166del`

## 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 4.765, GERP 1.62, 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 10 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.

*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 **389** 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 2024-11-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-11 |

## Associated conditions {#conditions}

[PHEX-related disorder](https://sugi.bio/atlas/disease/phex-related-disorder/).

**Reported phenotype names (ClinVar):** PHEX-related disorder, PHEX-related condition.

## Similar variants {#similar}

Related PHEX variant pages (same residue, condition, or type): [PHEX p.Gly6fs](/variant/phex-p-gly6fs), [PHEX p.Phe409fs](/variant/phex-p-phe409fs), [PHEX p.Arg166fs](/variant/phex-p-arg166fs), [PHEX p.Gln621fs](/variant/phex-p-gln621fs), [PHEX p.Glu217fs](/variant/phex-p-glu217fs), [PHEX p.Lys359fs](/variant/phex-p-lys359fs), [PHEX p.Asn110del](/variant/phex-p-asn110del), [PHEX c.118+1G>A](/variant/phex-c-118-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4949322). 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.*