# NM_182746.3(MCM4):c.2154G>A (p.Arg718=)

https://sugi.bio/variant/mcm4-p-arg718

## Summary

**MCM4 p.Arg718= (c.2154G>A)** is classified **Likely benign** in MCM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). Very rare (popmax 0.00136%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs1312065989 · 1 submitter · very rare (popmax 0.00136%, nfe)

## For patients & families {#patients}

This is a change in the MCM4 gene that is classified as likely benign — not considered disease-causing, 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 | [MCM4](https://sugi.bio/atlas/gene/MCM4/) |
| Protein change (HGVS p.) | p.Arg718= |
| Coding change (HGVS c.) | c.2154G>A |
| MANE Select transcript | [NM_182746](https://www.ncbi.nlm.nih.gov/nuccore/NM_182746) |
| dbSNP | [rs1312065989](https://www.ncbi.nlm.nih.gov/snp/rs1312065989/) |
| Variant type | single nucleotide variant |
| Location | chr8:47974751-47974751 (GRCh38) |
| ClinVar | [VCV2078690](https://www.ncbi.nlm.nih.gov/clinvar/variation/2078690/) |

**All HGVS expressions:** `LRG_1239:g.19549G>A`, `LRG_1239t1:c.2154G>A`, `NC_000008.10:g.48887311G>A`, `NC_000008.11:g.47974751G>A`, `NG_032967.1:g.19549G>A`, `NM_005914.4:c.2154G>A`, `NM_182746.3:c.2154G>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 1.265, GERP -0.33, phastCons 1 — weakly conserved position
- CADD: **PHRED 7.513**. 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 (G>T, Δ0.24 acceptor loss), 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 **0.00136%** (nfe) · FAF95 0.000803% · FAF99 0.00065% · 16/1,179,992 in the highest group · 17/1,614,184 alleles overall — very rare (popmax 0.00136%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00136% | 73,750 |
| South Asian | 0.0011% | 91,088 |

*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}

**MCM4** population constraint: LOEUF 0.806, pLI 9.9071e-10, missense-Z 0.024942. *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):

- **primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency** — Moderate (AR)

## Protein context {#protein}

Residue **718** lies in an α-helix; the mcm c-terminal aaa(+) atpase domain.

AlphaFold model confidence (whole protein): pLDDT 74.25, 14% of residues very-high.

**28 experimental structure(s)** (PDB): [6XTX](https://www.rcsb.org/structure/6XTX), [6XTY](https://www.rcsb.org/structure/6XTY), [7PFO](https://www.rcsb.org/structure/7PFO), [7PLO](https://www.rcsb.org/structure/7PLO), [7W1Y](https://www.rcsb.org/structure/7W1Y), [7W68](https://www.rcsb.org/structure/7W68).

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

*Describes the biological roles of MCM4 (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.*


### Pathways affected {#pathways}

MCM4 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of ATR in response to replication stress](https://reactome.org/content/detail/R-HSA-176187) | curated |
| [Activation of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68962) | curated |
| [Orc1 removal from chromatin](https://reactome.org/content/detail/R-HSA-68949) | curated |
| [Switching of origins to a post-replicative state](https://reactome.org/content/detail/R-HSA-69052) | curated |
| [Assembly of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68867) | electronic |
| [Unwinding of DNA](https://reactome.org/content/detail/R-HSA-176974) | electronic |

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

**Biological process:** DNA replication.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-10.

**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 | 2025-02-10 |

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

## Similar variants {#similar}

Related MCM4 variant pages (same residue, condition, or type): [MCM4 c.71-2A>G](/variant/mcm4-c-71-minus-2a-g), [MCM4 c.-74C>T](/variant/mcm4-c-minus-74c-t), [MCM4 c.*56G>A](/variant/mcm4-c-star-56g-a), [MCM4 p.Ala141Gly](/variant/mcm4-p-ala141gly), [MCM4 p.Ala436Thr](/variant/mcm4-p-ala436thr), [MCM4 p.Ala668Thr](/variant/mcm4-p-ala668thr), [MCM4 p.Ala685Val](/variant/mcm4-p-ala685val), [MCM4 p.Ala694Thr](/variant/mcm4-p-ala694thr).

### 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 2078690). 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.*