# NM_001383.6(DPH1):c.914_927del (p.Glu305fs)

https://sugi.bio/variant/dph1-p-glu305fs

## Summary

**DPH1 p.Glu305fs (c.914_927del)** is classified **Pathogenic** in DPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-30). Ultra-rare (popmax 0.0111%, eas).

**At a glance:** Pathogenic · review: Single submitter · rsID rs757405584 · 1 submitter · ultra-rare (popmax 0.0111%, eas)

## For patients & families {#patients}

This is a change in the DPH1 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 | [DPH1](https://sugi.bio/atlas/gene/DPH1/) |
| Protein change (HGVS p.) | p.Glu305fs |
| Coding change (HGVS c.) | c.914_927del |
| MANE Select transcript | [NM_001383](https://www.ncbi.nlm.nih.gov/nuccore/NM_001383) |
| dbSNP | [rs757405584](https://www.ncbi.nlm.nih.gov/snp/rs757405584/) |
| Variant type | Deletion |
| Location | chr17:2040512-2040525 (GRCh38) |
| ClinVar | [VCV1188796](https://www.ncbi.nlm.nih.gov/clinvar/variation/1188796/) |

**All HGVS expressions:** `NC_000017.10:g.1943806_1943819del`, `NC_000017.11:g.2040512_2040525del`, `NG_051946.1:g.15401_15414del`, `NM_001346574.1:c.866_879del`, `NM_001346575.1:c.833_846del`, `NM_001346576.2:c.509_522del`, `NM_001383.6:c.914_927del`, `NR_144474.2:n.1287_1300del`, `NR_144475.2:n.1254_1267del`, `NR_144476.2:n.1313_1326del`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.809, GERP 2.33, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.321, pLI 9.9258e-22. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 13**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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 assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0111%** (eas) · FAF95 0.00434% · FAF99 0.00276% · 5/44,884 in the highest group · 5/1,614,190 alleles overall — ultra-rare (popmax 0.0111%, eas).

*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}

**DPH1** population constraint: LOEUF 1.321, pLI 9.9258e-22, missense-Z -0.4356. *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):

- **developmental delay with short stature, dysmorphic facial features, and sparse hair** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.00, 81% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of DPH1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

DPH1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of diphthamide-EEF2](https://reactome.org/content/detail/R-HSA-5358493) | curated |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-09-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2019-09-30 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related DPH1 variant pages (same residue, condition, or type): [DPH1 p.Glu92fs](/variant/dph1-p-glu92fs), [DPH1 p.Tyr263del](/variant/dph1-p-tyr263del), [DPH1 p.Arg153fs](/variant/dph1-p-arg153fs), [DPH1 p.Pro169fs](/variant/dph1-p-pro169fs), [DPH1 p.His400fs](/variant/dph1-p-his400fs), [DPH1 p.Met268del](/variant/dph1-p-met268del), [DPH1 p.Pro217del](/variant/dph1-p-pro217del).

### 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 1188796). 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.*