# NM_205861.3(DHDDS):c.614G>A (p.Arg205Gln)

https://sugi.bio/variant/dhdds-p-arg205gln

## Summary

**DHDDS p.Arg205Gln (c.614G>A)** is classified **Pathogenic** in DHDDS (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-04-23). AlphaMissense: likely pathogenic (0.994); Absent from gnomAD v4.1; Associated with developmental delay and seizures with or without movement abnormalities.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1557447255 · 11 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DHDDS gene that is considered disease-causing, submitted by 11 submitters, and is linked to developmental delay and seizures with or without movement abnormalities.

*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/0016261/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.Arg205Gln |
| Coding change (HGVS c.) | c.614G>A |
| MANE Select transcript | [NM_205861](https://www.ncbi.nlm.nih.gov/nuccore/NM_205861) |
| dbSNP | [rs1557447255](https://www.ncbi.nlm.nih.gov/snp/rs1557447255/) |
| Variant type | single nucleotide variant |
| Location | chr1:26457862-26457862 (GRCh38) |
| ClinVar | [VCV570739](https://www.ncbi.nlm.nih.gov/clinvar/variation/570739/) |

**All HGVS expressions:** `NC_000001.10:g.26784353G>A`, `NC_000001.11:g.26457862G>A`, `NG_029786.1:g.30581G>A`, `NM_001243564.2:c.512G>A`, `NM_001243565.2:c.497G>A`, `NM_001319959.2:c.335G>A`, `NM_024887.4:c.614G>A`, `NM_205861.3:c.614G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.994) — concordant with the pathogenic call
- REVEL 0.825 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.637 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.24) — consistent with the pathogenic call
- Conservation: phyloP 9.901, GERP 2.02, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in DHDDS (of 1,940 modeled).
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.89** across the covering region of the MANE Select transcript (26,442,833–26,469,128), spanning 26,295 bp. Chi-square p 0.063. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.02**, acceptor gain **0.24**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.02**, acceptor gain **0.24**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **205** lies in a binding site; a UniProt-annotated variant site (in rp59; in a patient with congenital disorder of glycosylation); a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy; uncertain significance); a β-strand.

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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-23.

**Submitter consensus:** unanimous (11/11 Pathogenic).

**Submission history:** 11 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-04-06 |
| Fundacion Publica Galega de Medicina Xenomica, Servicio Galego de Saude | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-21 |
| Illumina Laboratory Services, Illumina | Pathogenic | criteria provided, single submitter | clinical testing | 2022-12-02 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-29 |
| Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-26 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-11 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-23 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-18 |

## Associated conditions {#conditions}

[developmental delay and seizures with or without movement abnormalities](https://sugi.bio/atlas/disease/developmental-delay-and-seizures-with-or-without-movement-abnormalities/), [retinitis pigmentosa 59](https://sugi.bio/atlas/disease/retinitis-pigmentosa-59/).

**Reported phenotype names (ClinVar):** Developmental delay and seizures with or without movement abnormalities, Retinitis pigmentosa 59, not provided, DHDDS-related disorders, none provided.

## Similar variants {#similar}

Related DHDDS variant pages (same residue, condition, or type): [DHDDS p.Arg205Trp](/variant/dhdds-p-arg205trp), [DHDDS p.Arg205=](/variant/dhdds-p-arg205), [DHDDS c.658-2A>G](/variant/dhdds-c-658-minus-2a-g), [DHDDS p.Arg211Gln](/variant/dhdds-p-arg211gln), [DHDDS p.Arg37Cys](/variant/dhdds-p-arg37cys), [DHDDS p.Arg37His](/variant/dhdds-p-arg37his), [DHDDS p.Arg37Ser](/variant/dhdds-p-arg37ser), [DHDDS p.Arg38His](/variant/dhdds-p-arg38his).

### 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 2026-07-14); 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 570739). 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.*