# NM_205861.3(DHDDS):c.616A>G (p.Thr206Ala)

https://sugi.bio/variant/dhdds-p-thr206ala

## Summary

**DHDDS p.Thr206Ala (c.616A>G)** is classified **Likely pathogenic** in DHDDS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-22). AlphaMissense: likely pathogenic (0.964); Very rare (popmax 6.84e-05%); Associated with retinitis pigmentosa.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs2124489724 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 6.84e-05%)

## For patients & families {#patients}

This is a change in the DHDDS gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to retinitis pigmentosa.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 238 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DHDDS is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Retinitis pigmentosa** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005694/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.Thr206Ala |
| Coding change (HGVS c.) | c.616A>G |
| MANE Select transcript | [NM_205861](https://www.ncbi.nlm.nih.gov/nuccore/NM_205861) |
| dbSNP | [rs2124489724](https://www.ncbi.nlm.nih.gov/snp/rs2124489724/) |
| Variant type | single nucleotide variant |
| Location | chr1:26457864-26457864 (GRCh38) |
| ClinVar | [VCV1297155](https://www.ncbi.nlm.nih.gov/clinvar/variation/1297155/) |

**All HGVS expressions:** `NC_000001.10:g.26784355A>G`, `NC_000001.11:g.26457864A>G`, `NG_029786.1:g.30583A>G`, `NM_001243564.2:c.514A>G`, `NM_001243565.2:c.499A>G`, `NM_001319959.2:c.337A>G`, `NM_024887.4:c.616A>G`, `NM_205861.3:c.616A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.964) — concordant with the pathogenic call
- REVEL 0.947 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.044 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.171, GERP 2.02, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.3**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): global (via dbSNP) **6.84e-05%** · 1/1,461,856 alleles overall — very rare (popmax 6.84e-05%).

*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 **206** lies in a UniProt-annotated variant site (in rp59; in a patient with congenital disorder of glycosylation); 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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-22.

**Submitter consensus:** unanimous (4/4 Likely pathogenic).

**Submission history:** 4 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Likely pathogenic | criteria provided, single submitter | curation | 2021-04-01 |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Likely pathogenic | criteria provided, single submitter | curation | 2022-05-04 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-07 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-22 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related DHDDS variant pages (same residue, condition, or type): [DHDDS c.658-2A>G](/variant/dhdds-c-658-minus-2a-g), [DHDDS p.Arg205Gln](/variant/dhdds-p-arg205gln), [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.Gly35Glu](/variant/dhdds-p-gly35glu), [DHDDS p.Lys42Glu](/variant/dhdds-p-lys42glu).

### 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 1297155). 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.*