# NM_014908.4(DOLK):c.843G>A (p.Arg281=)

https://sugi.bio/variant/dolk-p-arg281

## Summary

**DOLK p.Arg281= (c.843G>A)** is classified **Likely benign** in DOLK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-24). Very rare (popmax 0.000169%, nfe); Associated with DK1-congenital disorder of glycosylation.

**At a glance:** Likely benign · review: Single submitter · rsID rs1430371382 · 1 submitter · 1 linked condition · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the DOLK gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to DK1-congenital disorder of glycosylation.

*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 recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | DOLK is a diagnostic-grade gene on 17 Genomics England panels |

**Commonly reported features of DK1-CDG** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dilated cardiomyopathy — Very frequent (99-80%)
- Type I transferrin isoform profile — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Cardiomyocyte hypertrophy — Very frequent (99-80%)
- Seizure — Frequent (79-30%)
- Failure to thrive — Frequent (79-30%)
- Congestive heart failure — Frequent (79-30%)
- Elevated circulating hepatic transaminase concentration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012393/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DOLK](https://sugi.bio/atlas/gene/DOLK/) |
| Protein change (HGVS p.) | p.Arg281= |
| Coding change (HGVS c.) | c.843G>A |
| MANE Select transcript | [NM_014908](https://www.ncbi.nlm.nih.gov/nuccore/NM_014908) |
| dbSNP | [rs1430371382](https://www.ncbi.nlm.nih.gov/snp/rs1430371382/) |
| Variant type | single nucleotide variant |
| Location | chr9:128946461-128946461 (GRCh38) |
| ClinVar | [VCV1621119](https://www.ncbi.nlm.nih.gov/clinvar/variation/1621119/) |

**All HGVS expressions:** `LRG_744:g.6273G>A`, `NC_000009.11:g.131708740C>T`, `NC_000009.12:g.128946461C>T`, `NG_017009.1:g.6273G>A`, `NG_033111.1:g.3769C>T`, `NM_014908.4:c.843G>A`

## 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 0.425, GERP 0.609, phastCons 0.991 — weakly conserved position
- CADD: **PHRED 9.284**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.24 acceptor 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 (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,020 in the highest group · 3/1,613,970 alleles overall — very rare (popmax 0.000169%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |
| European (non-Finnish) (grpmax) | 0.000169% | 590,009 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**DOLK** population constraint: LOEUF 0.858, pLI 0.00023739, missense-Z 1.6948. *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):

- **DK1-congenital disorder of glycosylation** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.37, 74% of residues very-high.

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

*Describes the biological roles of DOLK (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:** DOLK's established molecular role includes dolichol kinase activity. In Reactome, DOLK is annotated in disease pathway(s) including **Defective DOLK causes DOLK-CDG**.

**Disease mechanism (Reactome):** DOLK loss or alteration is curated in [Defective DOLK causes DOLK-CDG](https://reactome.org/content/detail/R-HSA-4755583).

### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective DOLK causes DOLK-CDG](https://reactome.org/content/detail/R-HSA-4755583) | curated |
| [Synthesis of dolichyl-phosphate](https://reactome.org/content/detail/R-HSA-446199) | curated |

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

**Molecular function:** dolichol kinase activity.

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

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-24.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-24 |

## Associated conditions {#conditions}

[DK1-congenital disorder of glycosylation](https://sugi.bio/atlas/disease/dk1-congenital-disorder-of-glycosylation/).

**Reported phenotype names (ClinVar):** DK1-congenital disorder of glycosylation, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Im, DK1-CDG, DOLK-congenital disorder of glycosylation, Carbohydrate deficient glycoprotein syndrome type 1m, CDG Im, DK1 DEFICIENCY, DOLICHOL KINASE DEFICIENCY.

## Similar variants {#similar}

Related DOLK variant pages (same residue, condition, or type): [DOLK p.His408Asp](/variant/dolk-p-his408asp), [DOLK p.Met1Ile](/variant/dolk-p-met1ile), [DOLK p.Met1Thr](/variant/dolk-p-met1thr), [DOLK c.-194G>T](/variant/dolk-c-minus-194g-t), [DOLK c.-22G>A](/variant/dolk-c-minus-22g-a), [DOLK c.-269G>T](/variant/dolk-c-minus-269g-t), [DOLK p.Ala115Val](/variant/dolk-p-ala115val), [DOLK p.Ala129Ser](/variant/dolk-p-ala129ser).

### 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 1621119). 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.*