Is MBD4 p.Ser196Pro (c.586T>C) pathogenic?

MBD4 p.Ser196Pro (c.586T>C) is classified Uncertain significance in MBD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0885); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MBD4 p.Ser196Pro (c.586T>C)?

MBD4 p.Ser196Pro (c.586T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MBD4 p.Ser196Pro (c.586T>C) in the general population?

MBD4 p.Ser196Pro (c.586T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MBD4 p.Ser196Pro (c.586T>C)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

MBD4 p.Ser196Pro

c.586T>C · VCV4624440

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.6	GERP 0.18, phastCons 0.25
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	14.16	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MBD4
Protein: p.Ser196Pro
Coding: c.586T>C
MANE Select: NM_001276270
Type: single nucleotide variant
Location: chr3:129437058 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 196: 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)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MBD4 p.Ser196Ala Uncertain significance ★★ ⚠ same residue
MBD4 p.Ser196Ter Pathogenic ★ same residue
MBD4 p.Ser196Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MBD4 p.Ser196= Likely benign ★ same residue
MBD4 c.1544-1G>A Likely pathogenic ★★ same condition
MBD4 c.1544-1G>T Pathogenic/Likely pathogenic ★★ same condition
MBD4 c.1544-2A>G Likely pathogenic ★★ same condition
MBD4 c.335+1G>A 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-ser196pro (accessed [today's date]).

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