# NM_144988.4(ALG14):c.100dup (p.Arg34fs)

https://sugi.bio/variant/alg14-p-arg34fs

## Summary

**ALG14 p.Arg34fs (c.100dup)** is classified **Uncertain significance** in ALG14 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-05-11). Very rare (popmax 0.000169%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1064794986 · 1 submitter · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the ALG14 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ALG14](https://sugi.bio/atlas/gene/ALG14/) |
| Protein change (HGVS p.) | p.Arg34fs |
| Coding change (HGVS c.) | c.100dup |
| MANE Select transcript | [NM_144988](https://www.ncbi.nlm.nih.gov/nuccore/NM_144988) |
| dbSNP | [rs1064794986](https://www.ncbi.nlm.nih.gov/snp/rs1064794986/) |
| Variant type | Duplication |
| Location | chr1:95072798-95072799 (GRCh38) |
| ClinVar | [VCV421218](https://www.ncbi.nlm.nih.gov/clinvar/variation/421218/) |

**All HGVS expressions:** `NC_000001.10:g.95538358dup`, `NC_000001.11:g.95072802dup`, `NG_042044.1:g.5153dup`, `NM_001305242.2:c.100dup`, `NM_144988.4:c.100dup`, `NR_131032.2:n.153dup`

## 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 3.035, GERP 2.12, phastCons 0.998 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.055, pLI 7.0391e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 4**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 32.0**. 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.*
- 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 (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,046 in the highest group · 2/1,614,044 alleles overall — very rare (popmax 0.000169%, nfe).

*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}

**ALG14** population constraint: LOEUF 1.055, pLI 7.0391e-05, missense-Z 0.019929. *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):

- **congenital disorder of glycosylation** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.06, 74% of residues very-high.

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

*Describes the biological roles of ALG14 (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:** ALG14's established molecular role includes protein-membrane adaptor activity. In Reactome, ALG14 is annotated in disease pathway(s) including **Defective ALG14 causes ALG14-CMS**.

**Disease mechanism (Reactome):** ALG14 loss or alteration is curated in [Defective ALG14 causes ALG14-CMS](https://reactome.org/content/detail/R-HSA-5633231).

### Pathways affected {#pathways}

ALG14 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ALG14 causes ALG14-CMS](https://reactome.org/content/detail/R-HSA-5633231) | curated |
| [Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein](https://reactome.org/content/detail/R-HSA-446193) | curated |

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

**Molecular function:** protein-membrane adaptor activity.

**Biological process:** protein N-linked glycosylation, dolichol-linked oligosaccharide biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2016-05-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-05-11 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ALG14 variant pages (same residue, condition, or type): [ALG14 p.Leu159_Gly160insLeu](/variant/alg14-p-leu159-gly160insleu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 421218). 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.*