Is MBD4 p.Arg154Ser (c.462A>T) pathogenic?

MBD4 p.Arg154Ser (c.462A>T) is classified Uncertain significance in MBD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1266); Absent from gnomAD v4.1.

How common is MBD4 p.Arg154Ser (c.462A>T) in the general population?

MBD4 p.Arg154Ser (c.462A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MBD4 p.Arg154Ser (c.462A>T)?

AlphaMissense predicts likely benign (score 0.1266) — an in-silico prediction, not a clinical call.

MBD4 p.Arg154Ser

c.462A>T · VCV4770424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1266 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1266	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -5.57	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 -0.074	GERP -4.1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	5.782	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.Arg154Ser
Coding: c.462A>T
MANE Select: NM_001276270
Type: single nucleotide variant
Location: chr3:129437182 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 154: 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.Arg154= 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
MBD4 p.Arg400Ter 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-arg154ser (accessed [today's date]).

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