# NM_014208.3(DSPP):c.52G>T (p.Val18Phe)

https://sugi.bio/variant/dspp-p-val18phe

## Summary

**DSPP p.Val18Phe (c.52G>T)** is classified **Pathogenic** in DSPP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.216); Very rare (popmax 0.0011%, sas); Associated with DSPP-related disorders.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs121912987 · 4 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0011%, sas)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the DSPP gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 4 submitters, and is linked to DSPP-related disorders.

*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 | [DSPP](https://sugi.bio/atlas/gene/DSPP/) |
| Protein change (HGVS p.) | p.Val18Phe |
| Coding change (HGVS c.) | c.52G>T |
| MANE Select transcript | [NM_014208](https://www.ncbi.nlm.nih.gov/nuccore/NM_014208) |
| dbSNP | [rs121912987](https://www.ncbi.nlm.nih.gov/snp/rs121912987/) |
| Variant type | single nucleotide variant |
| Location | chr4:87612105-87612105 (GRCh38) |
| ClinVar | [VCV16856](https://www.ncbi.nlm.nih.gov/clinvar/variation/16856/) |

**All HGVS expressions:** `LRG_1242:g.8577G>T`, `LRG_1242t1:c.52G>T`, `NC_000004.11:g.88533257G>T`, `NC_000004.12:g.87612105G>T`, `NG_011595.1:g.8577G>T`, `NM_014208.3:c.52G>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.216) — ⚠ discordant with the pathogenic call
- REVEL 0.623 (indeterminate)
- SaProt LLR -7.525 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 1.377, GERP -1.06, phastCons 1 — weakly conserved position
- CADD: **PHRED 21.1**. 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.
- Pangolin: Δ**0.53** (loss), gain 0.01 / loss 0.53. 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 (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/91,052 in the highest group · 3/1,613,584 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,052 |
| European (non-Finnish) | 0.00017% | 589,890 |

*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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-07.

**Submitter consensus:** unanimous (6/6 Pathogenic).

**Submission history:** 6 submissions (2012–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2012-06-01 |
| Reference Center For Rare Oral And Dental Diseases, Crmr O-rares, Hôpitaux Universitaires De Strasbourg | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-03 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-16 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-07 |

## Associated conditions {#conditions}

[DSPP-related disorders](https://sugi.bio/atlas/disease/dspp-related-disorders/), [dentinogenesis imperfecta type 2](https://sugi.bio/atlas/disease/dentinogenesis-imperfecta-type-2/), [dentinogenesis imperfecta type 3](https://sugi.bio/atlas/disease/dentinogenesis-imperfecta-type-3/).

**Reported phenotype names (ClinVar):** DSPP-related disorders, Deafness, autosomal dominant nonsyndromic sensorineural 39, with dentinogenesis imperfecta 1, Dentinogenesis imperfecta type 2, Dentinogenesis imperfecta type 3, Monogenic hearing loss, Dentinogenesis imperfecta - Shield's type II, OPALESCENT DENTIN, OPALESCENT TEETH WITHOUT OSTEOGENESIS IMPERFECTA, CAPDEPONT TEETH, Dentinogenesis imperfecta without osteogenesis imperfecta.

### 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 16856). 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.*