# NM_001276270.2(MBD4):c.330dup (p.Ile111fs)

https://sugi.bio/variant/mbd4-p-ile111fs

## Summary

**MBD4 p.Ile111fs (c.330dup)** is classified **Pathogenic** in MBD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). Very rare (popmax 0.00068%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00068%, nfe)

## For patients & families {#patients}

This is a change in the MBD4 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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 | [MBD4](https://sugi.bio/atlas/gene/MBD4/) |
| Protein change (HGVS p.) | p.Ile111fs |
| Coding change (HGVS c.) | c.330dup |
| MANE Select transcript | [NM_001276270](https://www.ncbi.nlm.nih.gov/nuccore/NM_001276270) |
| Variant type | Duplication |
| Location | chr3:129437724-129437725 (GRCh38) |
| ClinVar | [VCV4052164](https://www.ncbi.nlm.nih.gov/clinvar/variation/4052164/) |

**All HGVS expressions:** `NC_000003.11:g.129156570dup`, `NC_000003.12:g.129437727dup`, `NG_023392.1:g.2603dup`, `NG_033106.1:g.7455dup`, `NM_001276270.2:c.330dup`, `NM_001276270.2:c.330dupT`, `NM_001276271.2:c.330dup`, `NM_001276272.2:c.330dup`, `NM_001276273.2:c.247+83dup`, `NM_003925.3:c.330dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 2.931, GERP 1.08, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.023, pLI 4.0105e-13. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 8**, so the transcript is predicted to undergo NMD.
- 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 **0.00068%** (nfe) · FAF95 0.000293% · FAF99 0.000211% · 8/1,176,570 in the highest group · 8/1,610,440 alleles overall — very rare (popmax 0.00068%, 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}

**MBD4** population constraint: LOEUF 1.023, pLI 4.0105e-13, missense-Z 1.1641. *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):

- **tumor predisposition syndrome 2** — Moderate (AR)
- **uveal melanoma** — Moderate (AD)

## Protein context {#protein}

Residue **111** lies in the mbd domain; a UniProt-annotated variant site (in tpds2; no mbd4 protein detected by immunohistochemical analysis in patient tumor tissue); a β-strand.

AlphaFold model confidence (whole protein): pLDDT 60.67, 33% of residues very-high.

**19 experimental structure(s)** (PDB): [2MOE](https://www.rcsb.org/structure/2MOE), [36XS](https://www.rcsb.org/structure/36XS), [3IHO](https://www.rcsb.org/structure/3IHO), [4DK9](https://www.rcsb.org/structure/4DK9), [4E9E](https://www.rcsb.org/structure/4E9E), [4E9F](https://www.rcsb.org/structure/4E9F).

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

*Describes the biological roles of MBD4 (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:** MBD4's established molecular role includes pyrimidine-specific mismatch base pair DNA N-glycosylase activity. p.Ile111fs falls in the mbd domain.


### Pathways affected {#pathways}

MBD4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cleavage of the damaged pyrimidine ](https://reactome.org/content/detail/R-HSA-110329) | curated |
| [Displacement of DNA glycosylase by APEX1](https://reactome.org/content/detail/R-HSA-110357) | curated |
| [Recognition and association of DNA glycosylase with site containing an affected pyrimidine](https://reactome.org/content/detail/R-HSA-110328) | curated |

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

**Molecular function:** pyrimidine-specific mismatch base pair DNA N-glycosylase activity.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-27.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-27 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related MBD4 variant pages (same residue, condition, or type): [MBD4 p.Ile111Leu](/variant/mbd4-p-ile111leu), [MBD4 p.Ile111Met](/variant/mbd4-p-ile111met), [MBD4 p.Arg378fs](/variant/mbd4-p-arg378fs), [MBD4 p.Asp392fs](/variant/mbd4-p-asp392fs), [MBD4 p.Lys84Ter](/variant/mbd4-p-lys84ter), [MBD4 p.Thr77fs](/variant/mbd4-p-thr77fs), [MBD4 p.Glu298fs](/variant/mbd4-p-glu298fs), [MBD4 p.Trp547fs](/variant/mbd4-p-trp547fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4052164). 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.*