# NM_000444.6(PHEX):c.1717G>C (p.Ala573Pro)

https://sugi.bio/variant/phex-p-ala573pro

## Summary

**PHEX p.Ala573Pro (c.1717G>C)** is classified **Pathogenic** in PHEX (ClinVar, Single submitter, 1 submitter; last evaluated 2015-06-04). AlphaMissense: likely pathogenic (0.9958); Absent from gnomAD v4.1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1057520756 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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.

*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.Ala573Pro |
| Coding change (HGVS c.) | c.1717G>C |
| MANE Select transcript | [NM_000444](https://www.ncbi.nlm.nih.gov/nuccore/NM_000444) |
| dbSNP | [rs1057520756](https://www.ncbi.nlm.nih.gov/snp/rs1057520756/) |
| Variant type | single nucleotide variant |
| Location | chrX:22219052-22219052 (GRCh38) |
| ClinVar | [VCV379848](https://www.ncbi.nlm.nih.gov/clinvar/variation/379848/) |

**All HGVS expressions:** `NC_000023.10:g.22237169G>C`, `NC_000023.11:g.22219052G>C`, `NG_007563.2:g.191249G>C`, `NM_000444.6:c.1717G>C`, `NM_001282754.2:c.1717G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9958) — concordant with the pathogenic call
- REVEL 0.891 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.671 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.778, GERP 2.53, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in PHEX (of 4,423 modeled).
- CADD: **PHRED 29.6**. 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 0.83** across the covering region of the MANE Select transcript (22,033,006–22,247,950), spanning 214,944 bp. Chi-square p 6.8e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.34 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code 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 **573** 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2015-06-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2015-06-04 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **573** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [PHEX p.Ala573fs](/variant/phex-p-ala573fs), [PHEX p.Ala573Asp](/variant/phex-p-ala573asp), [PHEX p.Ala573Val](/variant/phex-p-ala573val). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PHEX variant pages (same residue, condition, or type): [PHEX p.Ala573Asp](/variant/phex-p-ala573asp), [PHEX p.Ala573Val](/variant/phex-p-ala573val), [PHEX p.Ala573Thr](/variant/phex-p-ala573thr), [PHEX p.Ala573fs](/variant/phex-p-ala573fs), [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.1080-2A>G](/variant/phex-c-1080-minus-2a-g).

### 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 379848). 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.*