Is MBD4 p.Ser342Pro (c.1024T>C) pathogenic?

MBD4 p.Ser342Pro (c.1024T>C) is classified Benign in MBD4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-10). AlphaMissense: likely benign (0.0836); Common (popmax 12.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with tumor predisposition syndrome 2.

What condition is associated with MBD4 p.Ser342Pro (c.1024T>C)?

MBD4 p.Ser342Pro (c.1024T>C) is associated with tumor predisposition syndrome 2 (ClinVar).

How is MBD4-related tumor predisposition syndrome inherited?

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

What do computational predictors say about MBD4 p.Ser342Pro (c.1024T>C)?

AlphaMissense predicts likely benign (score 0.0836) — an in-silico prediction, not a clinical call.

MBD4 p.Ser342Pro

Q: How common is MBD4 p.Ser342Pro (c.1024T>C) in the general population?

MBD4 p.Ser342Pro (c.1024T>C) is common (popmax 12.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1024T>C · rs2307289 · VCV1268570

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0836 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tumor predisposition syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0836	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -1, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	12.47	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.7% African / African-American · 9,494/75,000 alleles

Filtering AF 12.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.4%

Overall 1.47% 23,658/1,614,052 alleles · common exomes 17,452/1,461,818 · genomes 6,206/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.7%	8
South Asian	10.4%	10
Remaining individualsnot grpmax-eligible	1.74%	57
East Asian	1.54%	65
Middle Eastern	1.04%	96
Admixed American	0.898%	111
European (non-Finnish)	0.194%	514
Finnishnot grpmax-eligible	0.0312%	3,201
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867

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.Ser342Pro
Coding: c.1024T>C
MANE Select: NM_001276270
dbSNP: rs2307289
Type: single nucleotide variant
Location: chr3:129436620 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 342: 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); a UniProt-annotated variant site (in)

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.Ser342Leu 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-ser342pro (accessed [today's date]).

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