# NM_001276270.2(MBD4):c.1239C>T (p.Ser413=)

https://sugi.bio/variant/mbd4-p-ser413

## Summary

**MBD4 p.Ser413= (c.1239C>T)** is classified **Uncertain significance** in MBD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-17). Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the MBD4 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 | [MBD4](https://sugi.bio/atlas/gene/MBD4/) |
| Protein change (HGVS p.) | p.Ser413= |
| Coding change (HGVS c.) | c.1239C>T |
| MANE Select transcript | [NM_001276270](https://www.ncbi.nlm.nih.gov/nuccore/NM_001276270) |
| Variant type | single nucleotide variant |
| Location | chr3:129434081-129434081 (GRCh38) |
| ClinVar | [VCV3692324](https://www.ncbi.nlm.nih.gov/clinvar/variation/3692324/) |

**All HGVS expressions:** `NC_000003.11:g.129152924G>A`, `NC_000003.12:g.129434081G>A`, `NG_033106.1:g.11099C>T`, `NM_001276270.2:c.1239C>T`, `NM_001276271.2:c.1257C>T`, `NM_001276272.2:c.1257C>T`, `NM_001276273.2:c.303C>T`, `NM_003925.3:c.1257C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.40) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.378, GERP 2.06, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 8.84**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.40**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 19 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.26** (loss), gain 0.00 / loss 0.26. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,972 in the highest group · 3/1,614,062 alleles overall — very rare (popmax 0.000254%, 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 **413** lies in a UniProt-annotated variant site (in tpds2; no mbd4 protein detected by immunohistochemical analysis in patient tumor tissue); a UniProt-annotated variant site (in uvm1); a UniProt-annotated variant site (in tpds2).

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.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-17.

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

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-17 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **413** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MBD4 p.Ser413fs](/variant/mbd4-p-ser413fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MBD4 variant pages (same residue, condition, or type): [MBD4 p.Ser413Cys](/variant/mbd4-p-ser413cys), [MBD4 c.1544-1G>A](/variant/mbd4-c-1544-minus-1g-a), [MBD4 c.1544-1G>T](/variant/mbd4-c-1544-minus-1g-t), [MBD4 c.1544-2A>G](/variant/mbd4-c-1544-minus-2a-g), [MBD4 c.335+1G>A](/variant/mbd4-c-335-plus-1g-a), [MBD4 p.Arg181Ter](/variant/mbd4-p-arg181ter), [MBD4 p.Arg400Ter](/variant/mbd4-p-arg400ter), [MBD4 p.Arg425Ter](/variant/mbd4-p-arg425ter).

### 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 3692324). 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.*