Is MBD4 p.Ala40= (c.120T>C) pathogenic?

MBD4 p.Ala40= (c.120T>C) is classified Benign/Likely benign in MBD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-09). Very rare (popmax 0.00133%, afr); Associated with tumor predisposition syndrome 2.

What condition is associated with MBD4 p.Ala40= (c.120T>C)?

MBD4 p.Ala40= (c.120T>C) is associated with tumor predisposition syndrome 2 (ClinVar).

How common is MBD4 p.Ala40= (c.120T>C) in the general population?

MBD4 p.Ala40= (c.120T>C) is very rare (popmax 0.00133%, afr) (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.Ala40=

c.120T>C · rs2530729036 · VCV2703867

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

tumor predisposition syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.095	GERP -3.4
Overall
CADD	3.047	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,914 alleles

Overall 6.22e-05% 1/1,607,936 alleles · very rare exomes 1/1,455,592 · genomes 0/152,344 · 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.Ala40=
Coding: c.120T>C
MANE Select: NM_001276270
dbSNP: rs2530729036
Type: single nucleotide variant
Location: chr3:129437935 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB

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.Ala40Thr Uncertain significance ★ ⚠ same residue
MBD4 c.104+1G>A Likely pathogenic ★★ same condition
MBD4 c.1544-1G>T Pathogenic/Likely pathogenic ★★ same condition
MBD4 p.Arg181Ter Pathogenic ★★ same condition
MBD4 p.Gln52Ter Pathogenic ★★ same condition
MBD4 p.Gln73Ter Pathogenic ★★ same condition
MBD4 p.Leu557Ter Pathogenic/Likely pathogenic ★★ same condition
MBD4 p.Ser321Ter Pathogenic/Likely pathogenic ★★ 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-ala40 (accessed [today's date]).

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