# NM_205861.3(DHDDS):c.374_377dup (p.Pro128fs)

https://sugi.bio/variant/dhdds-p-pro128fs

## Summary

**DHDDS p.Pro128fs (c.374_377dup)** is classified **Pathogenic** in DHDDS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-29). No gnomAD frequency available for this variant; Associated with retinitis pigmentosa 59.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2124425894 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DHDDS gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to retinitis pigmentosa 59.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015724/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DHDDS](https://sugi.bio/atlas/gene/DHDDS/) |
| Protein change (HGVS p.) | p.Pro128fs |
| Coding change (HGVS c.) | c.374_377dup |
| MANE Select transcript | [NM_205861](https://www.ncbi.nlm.nih.gov/nuccore/NM_205861) |
| dbSNP | [rs2124425894](https://www.ncbi.nlm.nih.gov/snp/rs2124425894/) |
| Variant type | Duplication |
| Location | chr1:26446365-26446366 (GRCh38) |
| ClinVar | [VCV1076541](https://www.ncbi.nlm.nih.gov/clinvar/variation/1076541/) |

**All HGVS expressions:** `NC_000001.10:g.26772857_26772860dup`, `NC_000001.11:g.26446366_26446369dup`, `NG_029786.1:g.19085_19088dup`, `NM_001243564.2:c.374_377dup`, `NM_001243565.2:c.324-1193_324-1190dup`, `NM_001319959.2:c.95_98dup`, `NM_024887.4:c.374_377dup`, `NM_205861.3:c.374_377dup`

## 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 2.682, GERP 1.11, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.536, pLI 0.90959), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**DHDDS** population constraint: LOEUF 0.536, pLI 0.90959, missense-Z 1.7803. *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):

- **DHDDS-CDG** — Definitive (AR)

## Protein context {#protein}

Residue **128** lies in a UniProt-annotated variant site (in rp59; in a patient with congenital disorder of glycosylation).

AlphaFold model confidence (whole protein): pLDDT 95.01, 90% of residues very-high.

**9 experimental structure(s)** (PDB): [6W2L](https://www.rcsb.org/structure/6W2L), [6Z1N](https://www.rcsb.org/structure/6Z1N), [7PAX](https://www.rcsb.org/structure/7PAX), [7PAY](https://www.rcsb.org/structure/7PAY), [7PB0](https://www.rcsb.org/structure/7PB0), [7PB1](https://www.rcsb.org/structure/7PB1).

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

*Describes the biological roles of DHDDS (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:** DHDDS's established molecular role includes ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity. In Reactome, DHDDS is annotated in disease pathway(s) including **Defective DHDDS causes RP59**.

**Disease mechanism (Reactome):** DHDDS loss or alteration is curated in [Defective DHDDS causes RP59](https://reactome.org/content/detail/R-HSA-4755609).

### Pathways affected {#pathways}

DHDDS participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective DHDDS causes RP59](https://reactome.org/content/detail/R-HSA-4755609) | curated |
| [Synthesis of dolichyl-phosphate](https://reactome.org/content/detail/R-HSA-446199) | curated |

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

**Molecular function:** ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific] activity.

**Biological process:** dolichyl diphosphate biosynthetic process, dolichyl monophosphate biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-02-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-02-29 |

## Associated conditions {#conditions}

[retinitis pigmentosa 59](https://sugi.bio/atlas/disease/retinitis-pigmentosa-59/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa 59.

## Similar variants {#similar}

Related DHDDS variant pages (same residue, condition, or type): [DHDDS p.Pro128=](/variant/dhdds-p-pro128), [DHDDS p.Val173fs](/variant/dhdds-p-val173fs), [DHDDS p.Trp171fs](/variant/dhdds-p-trp171fs), [DHDDS c.180+6dup](/variant/dhdds-c-180-plus-6dup), [DHDDS c.658-11_658-9dup](/variant/dhdds-c-658-minus-11-658-minus-9dup), [DHDDS c.766-6dup](/variant/dhdds-c-766-minus-6dup), [DHDDS c.658-2A>G](/variant/dhdds-c-658-minus-2a-g), [DHDDS p.Arg205Gln](/variant/dhdds-p-arg205gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1076541). 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.*