# NM_205861.3(DHDDS):c.176C>T (p.Ala59Val)

https://sugi.bio/variant/dhdds-p-ala59val

## Summary

**DHDDS p.Ala59Val (c.176C>T)** is classified **Uncertain significance** in DHDDS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely pathogenic (0.7755); Absent from gnomAD v4.1; Associated with retinitis pigmentosa 59.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DHDDS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Ala59Val |
| Coding change (HGVS c.) | c.176C>T |
| MANE Select transcript | [NM_205861](https://www.ncbi.nlm.nih.gov/nuccore/NM_205861) |
| Variant type | single nucleotide variant |
| Location | chr1:26438280-26438280 (GRCh38) |
| ClinVar | [VCV4745745](https://www.ncbi.nlm.nih.gov/clinvar/variation/4745745/) |

**All HGVS expressions:** `NC_000001.10:g.26764771C>T`, `NC_000001.11:g.26438280C>T`, `NG_029786.1:g.10999C>T`, `NM_001243564.2:c.176C>T`, `NM_001243565.2:c.176C>T`, `NM_001319959.2:c.-127C>T`, `NM_024887.4:c.176C>T`, `NM_205861.3:c.176C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7755)
- REVEL 0.261 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -6.755 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 7.588, GERP 2.01, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.3**. 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 0.58** across the covering region of the MANE Select transcript (26,432,946–26,442,832), spanning 9,886 bp. Chi-square p 3.6e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.99 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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 **59** lies in an α-helix.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-02 |

## 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.Ala59=](/variant/dhdds-p-ala59), [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).

### 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 4745745). 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.*