Is MBD4 p.Pro87Ser (c.259C>T) pathogenic?

MBD4 p.Pro87Ser (c.259C>T) is classified Uncertain significance in MBD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-09). AlphaMissense: likely benign (0.1933); Very rare (popmax 8.47e-05%, nfe).

How common is MBD4 p.Pro87Ser (c.259C>T) in the general population?

MBD4 p.Pro87Ser (c.259C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MBD4 p.Pro87Ser (c.259C>T)?

AlphaMissense predicts likely benign (score 0.1933) — an in-silico prediction, not a clinical call.

MBD4 p.Pro87Ser

c.259C>T · VCV3692859

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1933	likely benign
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -14.99	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3	GERP -0.14, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	22.3	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 8.47e-05% European (non-Finnish) · 1/1,180,014 alleles

Overall 6.2e-05% 1/1,613,990 alleles · very rare exomes 0/1,461,842 · genomes 1/152,148 · 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.Pro87Ser
Coding: c.259C>T
MANE Select: NM_001276270
Type: single nucleotide variant
Location: chr3:129437796 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 87: the mbd domain; a UniProt-annotated variant site (in tpds2; no mbd4 protein detected by immunohistochemical analysis in patient tumor tissue)

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

Similar variants

MBD4 p.Pro87Leu Uncertain significance ★★ ⚠ same residue
MBD4 p.Pro87= Likely benign ★ same residue
MBD4 c.104+1G>A Likely pathogenic ★★ same type
MBD4 c.1544-1G>A Likely pathogenic ★★ same type
MBD4 c.1544-1G>T Pathogenic/Likely pathogenic ★★ same type
MBD4 c.1544-2A>G Likely pathogenic ★★ same type
MBD4 c.335+1G>A Likely pathogenic ★★ same type
MBD4 p.Arg181Ter Pathogenic ★★ same type

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-pro87ser (accessed [today's date]).

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