# NM_014208.3(DSPP):c.53T>A (p.Val18Asp)

https://sugi.bio/variant/dspp-p-val18asp

## Summary

**DSPP p.Val18Asp (c.53T>A)** is classified **Likely pathogenic** in DSPP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-02). AlphaMissense: likely pathogenic (0.833); Absent from gnomAD v4.1; Associated with dentinogenesis imperfecta type 2.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1727745724 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DSPP gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to dentinogenesis imperfecta type 2.

*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 dominant |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |

**Commonly reported features of Dentinogenesis imperfecta** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Obliteration of the pulp chamber — Very frequent (99-80%)
- Abnormality of the dental root — Very frequent (99-80%)
- Grayish enamel — Frequent (79-30%)
- Odontodysplasia — Frequent (79-30%)
- Joint hypermobility — Frequent (79-30%)
- Generalized hypoplasia of dental enamel — Frequent (79-30%)
- Yellow-brown discoloration of the teeth — Frequent (79-30%)
- Abnormality of the dental pulp — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012796/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DSPP](https://sugi.bio/atlas/gene/DSPP/) |
| Protein change (HGVS p.) | p.Val18Asp |
| Coding change (HGVS c.) | c.53T>A |
| dbSNP | [rs1727745724](https://www.ncbi.nlm.nih.gov/snp/rs1727745724/) |
| Variant type | single nucleotide variant |
| Location | chr4:87612106-87612106 (GRCh38) |
| ClinVar | [VCV1320199](https://www.ncbi.nlm.nih.gov/clinvar/variation/1320199/) |

**All HGVS expressions:** `LRG_1242:g.8578T>A`, `LRG_1242t1:c.53T>A`, `NC_000004.11:g.88533258T>A`, `NC_000004.12:g.87612106T>A`, `NG_011595.1:g.8578T>A`, `NM_014208.3:c.53T>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.833) — concordant with the pathogenic call
- REVEL 0.742 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.881 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.784, GERP 1.68, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.8**. 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 0.98** across the covering region of the MANE Select transcript (87,610,909–87,614,269), spanning 3,360 bp. Chi-square p 0.63. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **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.*

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-10-02.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-10-02 |

## Associated conditions {#conditions}

[dentinogenesis imperfecta type 2](https://sugi.bio/atlas/disease/dentinogenesis-imperfecta-type-2/).

**Reported phenotype names (ClinVar):** Dentinogenesis imperfecta type 2, Dentinogenesis imperfecta without osteogenesis imperfecta, Hereditary Opalescent Dentin, OPALESCENT DENTIN, OPALESCENT TEETH WITHOUT OSTEOGENESIS IMPERFECTA, CAPDEPONT TEETH, Dentinogenesis imperfecta - Shield's type II.

### 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 1320199). 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.*