# NM_002361.4(MAG):c.439C>G (p.Pro147Ala)

https://sugi.bio/variant/mag-p-pro147ala

## Summary

**MAG p.Pro147Ala (c.439C>G)** is classified **Uncertain significance** in MAG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-01). AlphaMissense: likely benign (0.0658); Ultra-rare (popmax 0.0553%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs202205105 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0553%, nfe)

## For patients & families {#patients}

This is a change in the MAG gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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 | [MAG](https://sugi.bio/atlas/gene/MAG/) |
| Protein change (HGVS p.) | p.Pro147Ala |
| Coding change (HGVS c.) | c.439C>G |
| MANE Select transcript | [NM_000400](https://www.ncbi.nlm.nih.gov/nuccore/NM_000400) (variant reported on NM_002361) |
| dbSNP | [rs202205105](https://www.ncbi.nlm.nih.gov/snp/rs202205105/) |
| Variant type | single nucleotide variant |
| Location | chr19:35299577-35299577 (GRCh38) |
| ClinVar | [VCV969102](https://www.ncbi.nlm.nih.gov/clinvar/variation/969102/) |

**All HGVS expressions:** `NC_000019.10:g.35299577C>G`, `NC_000019.9:g.35790480C>G`, `NG_034078.1:g.12492C>G`, `NM_001199216.2:c.364C>G`, `NM_002361.4:c.439C>G`, `NM_080600.3:c.439C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0658)
- REVEL 0.318 (indeterminate)
- SaProt LLR -6.417 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 1.775, GERP -0.876, phastCons 0.849 — weakly conserved position
- CADD: **PHRED 15.02**. 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** — 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): grpmax **0.0553%** (nfe) · FAF95 0.0517% · FAF99 0.0504% · 648/1,171,310 in the highest group · 779/1,601,352 alleles overall — ultra-rare (popmax 0.0553%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.167% | 599 |
| Finnish (not grpmax-eligible) | 0.0831% | 1,204 |
| European (non-Finnish) (grpmax) | 0.0553% | 1,808 |
| Remaining individuals (not grpmax-eligible) | 0.0259% | 3,863 |
| African / African-American | 0.0134% | 7,450 |
| Admixed American | 0.00337% | 29,709 |
| South Asian | 0.00111% | 89,940 |

Ashkenazi Jewish 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}

**MAG** population constraint: ClinGen dosage — haploinsufficiency 30, triplosensitivity 40 (0–3 scale). *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):

- **complex hereditary spastic paraplegia** — Definitive (AR)
- **xeroderma pigmentosum group D** — Definitive (AR)

## Protein context {#protein}

Residue **147** lies in the helicase atp-binding domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 87.74, 53% of residues very-high.

**55 experimental structure(s)** (PDB): [28JM](https://www.rcsb.org/structure/28JM), [28JS](https://www.rcsb.org/structure/28JS), [28JV](https://www.rcsb.org/structure/28JV), [28KE](https://www.rcsb.org/structure/28KE), [29VF](https://www.rcsb.org/structure/29VF), [29WD](https://www.rcsb.org/structure/29WD).

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

*Describes the biological roles of MAG (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:** MAG's established molecular role includes protein-macromolecule adaptor activity. p.Pro147Ala falls in the helicase atp-binding domain. In Reactome, MAG is annotated in disease pathway(s) including **Formation of HIV elongation complex in the absence of HIV Tat**, **Formation of HIV-1 elongation complex containing HIV-1 Tat**.

**Disease mechanism (Reactome):** MAG loss or alteration is curated in [Formation of HIV elongation complex in the absence of HIV Tat](https://reactome.org/content/detail/R-HSA-167152), [Formation of HIV-1 elongation complex containing HIV-1 Tat](https://reactome.org/content/detail/R-HSA-167200), [Formation of the HIV-1 Early Elongation Complex](https://reactome.org/content/detail/R-HSA-167158).

### Pathways affected {#pathways}

MAG participates in **30 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Formation of HIV elongation complex in the absence of HIV Tat](https://reactome.org/content/detail/R-HSA-167152) | electronic |
| ⚕ [Formation of HIV-1 elongation complex containing HIV-1 Tat](https://reactome.org/content/detail/R-HSA-167200) | electronic |
| ⚕ [Formation of the HIV-1 Early Elongation Complex](https://reactome.org/content/detail/R-HSA-167158) | electronic |
| ⚕ [HIV Transcription Initiation](https://reactome.org/content/detail/R-HSA-167161) | electronic |
| ⚕ [RNA Pol II CTD phosphorylation and interaction with CE during HIV infection](https://reactome.org/content/detail/R-HSA-167160) | electronic |
| ⚕ [RNA Polymerase II HIV Promoter Escape](https://reactome.org/content/detail/R-HSA-167162) | electronic |
| ⚕ [Tat-mediated elongation of the HIV-1 transcript](https://reactome.org/content/detail/R-HSA-167246) | electronic |
| ⚕ [Transcription of the HIV genome](https://reactome.org/content/detail/R-HSA-167172) | electronic |
| [Dual Incision in GG-NER](https://reactome.org/content/detail/R-HSA-5696400) | curated |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Formation of Incision Complex in GG-NER](https://reactome.org/content/detail/R-HSA-5696395) | curated |
| [Formation of RNA Pol II elongation complex ](https://reactome.org/content/detail/R-HSA-112382) | curated |
| [Formation of TC-NER Pre-Incision Complex](https://reactome.org/content/detail/R-HSA-6781823) | curated |
| [Formation of the Early Elongation Complex](https://reactome.org/content/detail/R-HSA-113418) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [RNA Pol II CTD phosphorylation and interaction with CE](https://reactome.org/content/detail/R-HSA-77075) | curated |
| [RNA Polymerase I Promoter Escape](https://reactome.org/content/detail/R-HSA-73772) | curated |
| [RNA Polymerase I Transcription Initiation](https://reactome.org/content/detail/R-HSA-73762) | curated |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Promoter Escape](https://reactome.org/content/detail/R-HSA-73776) | curated |
| [RNA Polymerase II Transcription Elongation](https://reactome.org/content/detail/R-HSA-75955) | curated |
| [RNA Polymerase II Transcription Initiation](https://reactome.org/content/detail/R-HSA-75953) | curated |
| [RNA Polymerase II Transcription Initiation And Promoter Clearance](https://reactome.org/content/detail/R-HSA-76042) | curated |
| [RNA Polymerase II Transcription Pre-Initiation And Promoter Opening](https://reactome.org/content/detail/R-HSA-73779) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |
| [mRNA Capping](https://reactome.org/content/detail/R-HSA-72086) | curated |
| [Cytosolic iron-sulfur cluster assembly](https://reactome.org/content/detail/R-HSA-2564830) | electronic |
| [NoRC negatively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-427413) | electronic |
| [RNA Polymerase I Transcription Termination](https://reactome.org/content/detail/R-HSA-73863) | electronic |

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

**Molecular function:** protein-macromolecule adaptor activity, 5'-3' DNA helicase activity.

**Biological process:** transcription-coupled nucleotide-excision repair, nucleotide-excision repair, regulation of transcription by RNA polymerase II, transcription by RNA polymerase II, transcription initiation at RNA polymerase II promoter, apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-11-01.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-23 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-01 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [hereditary spastic paraplegia 75](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-75/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Hereditary spastic paraplegia 75, Spastic paraplegia 75, autosomal recessive.

## Same-residue context {#hotspot}

Residue **147** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ERCC2 p.Gln147Ter](/variant/ercc2-p-gln147ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MAG variant pages (same residue, condition, or type): [ERCC2 p.Gln147Lys](/variant/ercc2-p-gln147lys), [ERCC2 p.Gln147=](/variant/ercc2-p-gln147), [ERCC2 p.Gln147Ter](/variant/ercc2-p-gln147ter), [ERCC2 p.Ala725Pro](/variant/ercc2-p-ala725pro), [ERCC2 p.Arg616Pro](/variant/ercc2-p-arg616pro), [MAG p.Arg508Ter](/variant/mag-p-arg508ter), [ERCC2 p.Ala108Thr](/variant/ercc2-p-ala108thr), [ERCC2 p.Ala144Val](/variant/ercc2-p-ala144val).

### 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 969102). 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.*