# NM_015958.3(DPH5):c.728_729dup (p.Asp244fs)

https://sugi.bio/variant/dph5-p-asp244fs

## Summary

**DPH5 p.Asp244fs (c.728_729dup)** is classified **Uncertain significance** in DPH5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-08). Very rare (popmax 0.00267%, afr); Associated with neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the DPH5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties.

*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 | [DPH5](https://sugi.bio/atlas/gene/DPH5/) |
| Protein change (HGVS p.) | p.Asp244fs |
| Coding change (HGVS c.) | c.728_729dup |
| MANE Select transcript | [NM_015958](https://www.ncbi.nlm.nih.gov/nuccore/NM_015958) |
| Variant type | Microsatellite |
| Location | chr1:100990536-100990537 (GRCh38) |
| ClinVar | [VCV3779282](https://www.ncbi.nlm.nih.gov/clinvar/variation/3779282/) |

**All HGVS expressions:** `NC_000001.10:g.101456093CA[3]`, `NC_000001.11:g.100990537CA[3]`, `NM_001077394.2:c.728_729dup`, `NM_001077395.2:c.725_726dup`, `NM_015958.3:c.728_729dup`

## Computational & population evidence {#evidence}

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

- **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 2.727, GERP 1.42, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.295, pLI 1.2937e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (8 of 8)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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 **0.00267%** (afr) · FAF95 0.000442% · FAF99 0.000166% · 2/75,032 in the highest group · 2/1,461,864 alleles overall — very rare (popmax 0.00267%, 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.*

## Gene constraint & dosage {#gene-context}

**DPH5** population constraint: LOEUF 1.295, pLI 1.2937e-06, missense-Z 0.75845. *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):

- **neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties** — Limited (AR)

## Protein context {#protein}

Residue **244** lies in a UniProt-annotated variant site (in nedsff; loss of function in diphthamide biosynthesis shown in a yeast assay system).

AlphaFold model confidence (whole protein): pLDDT 92.20, 81% of residues very-high.

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

*Describes the biological roles of DPH5 (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.*

**How this variant is thought to act:** DPH5's established molecular role includes diphthine methyl ester synthase activity.


### Pathways affected {#pathways}

DPH5 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** diphthine methyl ester synthase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2023-04-08 |

## Associated conditions {#conditions}

[neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties](https://sugi.bio/atlas/disease/neurodevelopmental-disorder-with-short-stature-prominent-forehead-and-feeding-difficulties/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties, DPH5-related diphthamide-deficiency syndrome.

## Similar variants {#similar}

Related DPH5 variant pages (same residue, condition, or type): [DPH5 p.Asp244Asn](/variant/dph5-p-asp244asn), [DPH5 p.His260Arg](/variant/dph5-p-his260arg), [DPH5 p.Pro104Thr](/variant/dph5-p-pro104thr), [DPH5 c.260+1G>T](/variant/dph5-c-260-plus-1g-t), [DPH5 p.Ala223Val](/variant/dph5-p-ala223val), [DPH5 p.Arg224Ser](/variant/dph5-p-arg224ser), [DPH5 p.Leu163Pro](/variant/dph5-p-leu163pro), [DPH5 p.Leu7Phe](/variant/dph5-p-leu7phe).

### 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 3779282). 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.*