Is MBD4 p.Ile69= (c.207C>T) pathogenic?

MBD4 p.Ile69= (c.207C>T) is classified Benign/Likely benign in MBD4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-09). Very rare (popmax 0.0028%, nfe); Associated with tumor predisposition syndrome 2.

What condition is associated with MBD4 p.Ile69= (c.207C>T)?

MBD4 p.Ile69= (c.207C>T) is associated with tumor predisposition syndrome 2 (ClinVar).

How common is MBD4 p.Ile69= (c.207C>T) in the general population?

MBD4 p.Ile69= (c.207C>T) is very rare (popmax 0.0028%, nfe) (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.Ile69=

c.207C>T · rs745423464 · VCV1986261

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

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 0.35	GERP -3.9
Overall
CADD	6.691	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 33/1,179,656 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00248% 40/1,613,812 alleles · very rare exomes 40/1,461,456 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00625%	16,012
European (non-Finnish)grpmax	0.0028%	35,747
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00133%	75,066
South Asian	0.0011%	91,072

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile69=
Coding: c.207C>T
MANE Select: NM_001276270
dbSNP: rs745423464
Type: single nucleotide variant
Location: chr3:129437848 (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.Ile69Val 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-ile69 (accessed [today's date]).

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