Is MBD4 p.Ser282fs (c.844dup) pathogenic?

MBD4 p.Ser282fs (c.844dup) is classified Pathogenic in MBD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-03). Very rare (popmax 0.00223%, eas); Associated with tumor predisposition syndrome 2.

What condition is associated with MBD4 p.Ser282fs (c.844dup)?

MBD4 p.Ser282fs (c.844dup) is associated with tumor predisposition syndrome 2 (ClinVar).

How common is MBD4 p.Ser282fs (c.844dup) in the general population?

MBD4 p.Ser282fs (c.844dup) is very rare (popmax 0.00223%, eas) (gnomAD).

How is MBD4-related tumor predisposition syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MBD4 p.Ser282fs

c.844dup · VCV4856754

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

tumor predisposition syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.3	GERP -3.5

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Overall 6.2e-05% 1/1,614,148 alleles · very rare exomes 1/1,461,846 · genomes 0/152,302 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MBD4
Protein: p.Ser282fs
Coding: c.844dup
MANE Select: NM_001276270
Type: Duplication
Location: chr3:129436799 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 282: 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)

Full MBD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tumor predisposition syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MBD4-related tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

MBD4 p.Asn206Ter Pathogenic ★★ same condition
MBD4 p.Glu314fs Pathogenic/Likely pathogenic ★★ same condition
MBD4 p.Ser413fs Pathogenic ★★ same condition
MBD4 p.Thr77fs Pathogenic ★★ same condition
MBD4 p.Ile237fs Pathogenic ★ same condition
MBD4 p.Ser282Cys Uncertain significance ★ ⚠ same residue
MBD4 p.Ser282Thr Uncertain significance ★ ⚠ same residue
MBD4 c.335+9dup Likely benign ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mbd4-p-ser282fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown