# NM_004407.4(DMP1):c.658C>A (p.Pro220Thr)

https://sugi.bio/variant/dmp1-p-pro220thr

## Summary

**DMP1 p.Pro220Thr (c.658C>A)** is classified **Uncertain significance** in DMP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.2045); Very rare (popmax 0.004%, afr); Associated with hypophosphatemic rickets, autosomal recessive, 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs367695473 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the DMP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hypophosphatemic rickets, autosomal recessive, 1.

*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) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |

**Commonly reported features of Autosomal recessive hypophosphatemic rickets** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypophosphatemic rickets — Obligate (100%)
- Renal phosphate wasting — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Delayed eruption of teeth — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Skeletal dysplasia — Very frequent (99-80%)
- Bone pain — Very frequent (99-80%)
- Osteomalacia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018416/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DMP1](https://sugi.bio/atlas/gene/DMP1/) |
| Protein change (HGVS p.) | p.Pro220Thr |
| Coding change (HGVS c.) | c.658C>A |
| dbSNP | [rs367695473](https://www.ncbi.nlm.nih.gov/snp/rs367695473/) |
| Variant type | single nucleotide variant |
| Location | chr4:87662436-87662436 (GRCh38) |
| ClinVar | [VCV349975](https://www.ncbi.nlm.nih.gov/clinvar/variation/349975/) |

**All HGVS expressions:** `NC_000004.11:g.88583588C>A`, `NC_000004.12:g.87662436C>A`, `NG_008988.1:g.17135C>A`, `NM_001079911.3:c.610C>A`, `NM_004407.4:c.658C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2045)
- REVEL 0.296 (indeterminate)
- SaProt LLR -5.471 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 6.089, GERP 1.48, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.5**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.004%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,990 in the highest group · 3/152,148 alleles overall — very rare (popmax 0.004%, afr).

*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.*

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-13.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |

## Associated conditions {#conditions}

[hypophosphatemic rickets, autosomal recessive, 1](https://sugi.bio/atlas/disease/hypophosphatemic-rickets-autosomal-recessive-1/).

**Reported phenotype names (ClinVar):** Hypophosphatemic rickets, autosomal recessive, 1, HYPOPHOSPHATEMIA, AUTOSOMAL RECESSIVE.

### 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 349975). 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.*