# NM_014208.3(DSPP):c.1060C>T (p.Arg354Cys)

https://sugi.bio/variant/dspp-p-arg354cys

## Summary

**DSPP p.Arg354Cys (c.1060C>T)** is classified **Conflicting classifications of pathogenicity** in DSPP (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.172); Rare (popmax 0.871%, sas); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs61731011 · 10 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.871%, sas)

## For patients & families {#patients}

This is a change in the DSPP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 10 submitters, and is linked to Inborn genetic diseases.

*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.Arg354Cys |
| Coding change (HGVS c.) | c.1060C>T |
| dbSNP | [rs61731011](https://www.ncbi.nlm.nih.gov/snp/rs61731011/) |
| Variant type | single nucleotide variant |
| Location | chr4:87613246-87613246 (GRCh38) |
| ClinVar | [VCV260354](https://www.ncbi.nlm.nih.gov/clinvar/variation/260354/) |

**All HGVS expressions:** `LRG_1242:g.9718C>T`, `LRG_1242t1:c.1060C>T`, `NC_000004.11:g.88534398C>T`, `NC_000004.12:g.87613246C>T`, `NG_011595.1:g.9718C>T`, `NM_014208.3:c.1060C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.172)
- REVEL 0.27 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.829 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.586, GERP -2.2, phastCons 0.003 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 17.43**. 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 (gnomAD v4.1): grpmax **0.871%** (sas) · FAF95 0.821% · FAF99 0.8% · 793/91,060 in the highest group · 8,013/1,613,718 alleles overall — rare (popmax 0.871%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.871% | 115 |
| European (non-Finnish) | 0.536% | 187 |
| Middle Eastern | 0.445% | 225 |
| Amish (not grpmax-eligible) | 0.439% | 228 |
| Remaining individuals (not grpmax-eligible) | 0.432% | 232 |
| Admixed American | 0.383% | 261 |
| Finnish (not grpmax-eligible) | 0.327% | 306 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.196% | 510 |
| East Asian | 0.0824% | 1,213 |
| African / African-American | 0.08% | 1,250 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-19.

**Submitter consensus:** conflicting (6 Likely benign, 2 Benign, 2 Uncertain significance).

**Submission history:** 10 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2019-12-09 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-05-14 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-04-14 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-06-11 |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2017-07-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-19 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-01 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [deafness, autosomal dominant 39, with dentinogenesis imperfecta 1](https://sugi.bio/atlas/disease/deafness-autosomal-dominant-39-with-dentinogenesis-imperfecta-1/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not specified, not provided, Deafness, autosomal dominant 39, with dentinogenesis imperfecta 1, AllHighlyPenetrant, none provided, DFNA39/DENTINOGENESIS IMPERFECTA 1 SYNDROME, DFNA39/DGI1 SYNDROME, DGI1/DFNA39 SYNDROME.

### 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 260354). 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.*