# NM_000444.6(PHEX):c.1701A>C (p.Arg567=)

https://sugi.bio/variant/phex-p-arg567

## Summary

**PHEX p.Arg567= (c.1701A>C)** is classified **Likely pathogenic** in PHEX (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-12). Absent from gnomAD v4.1; Associated with X-linked dominant hypophosphatemic rickets.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2518659982 · 2 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PHEX gene that is considered likely disease-causing, submitted by 2 submitters, 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.Arg567= |
| Coding change (HGVS c.) | c.1701A>C |
| MANE Select transcript | [NM_000444](https://www.ncbi.nlm.nih.gov/nuccore/NM_000444) |
| dbSNP | [rs2518659982](https://www.ncbi.nlm.nih.gov/snp/rs2518659982/) |
| Variant type | single nucleotide variant |
| Location | chrX:22219036-22219036 (GRCh38) |
| ClinVar | [VCV2506512](https://www.ncbi.nlm.nih.gov/clinvar/variation/2506512/) |

**All HGVS expressions:** `NC_000023.10:g.22237153A>C`, `NC_000023.11:g.22219036A>C`, `NG_007563.2:g.191233A>C`, `NG_007563.3:g.191713A>C`, `NM_000444.6:c.1701A>C`, `NM_001282754.2:c.1701A>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.41) — consistent with the pathogenic call
- Conservation: phyloP 5.699, GERP 2.39, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.01**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.41**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.41**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.33** (loss), gain 0.01 / loss 0.33. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **567** lies in the peptidase m13 domain; a UniProt-annotated variant site (in xlhrd).

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

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-12.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2024-04-30 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-12 |

## 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, Hypophosphatemia, vitamin D-resistant rickets, Vitamin D-resistant rickets,  X-linked, HYPOPHOSPHATEMIC VITAMIN D-RESISTANT RICKETS.

## Same-residue context {#hotspot}

Residue **567** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [PHEX p.Arg567Ter](/variant/phex-p-arg567ter), [PHEX p.Arg567Pro](/variant/phex-p-arg567pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PHEX variant pages (same residue, condition, or type): [PHEX p.Arg567Ter](/variant/phex-p-arg567ter), [PHEX p.Arg567Gln](/variant/phex-p-arg567gln), [PHEX p.Arg567Pro](/variant/phex-p-arg567pro), [PHEX c.1079+1G>A](/variant/phex-c-1079-plus-1g-a), [PHEX c.1079+2T>G](/variant/phex-c-1079-plus-2t-g), [PHEX c.1080-1G>A](/variant/phex-c-1080-minus-1g-a), [PHEX c.1080-3C>G](/variant/phex-c-1080-minus-3c-g), [PHEX c.1173+1G>A](/variant/phex-c-1173-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 2506512). 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.*