Is MBD4 p.Val484Ala (c.1451T>C) pathogenic?

MBD4 p.Val484Ala (c.1451T>C) is classified Uncertain significance in MBD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-13). AlphaMissense: likely benign (0.1196); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MBD4 p.Val484Ala (c.1451T>C)?

MBD4 p.Val484Ala (c.1451T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MBD4 p.Val484Ala (c.1451T>C) in the general population?

MBD4 p.Val484Ala (c.1451T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MBD4 p.Val484Ala (c.1451T>C)?

AlphaMissense predicts likely benign (score 0.1196) — an in-silico prediction, not a clinical call.

MBD4 p.Val484Ala

c.1451T>C · rs1056697984 · VCV2274349

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1196 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1196	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -6.52	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 0.82	GERP -1.9, phastCons 0.01
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	17.07	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V490A vs ClinVar V484A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.2e-05% 1/1,614,194 alleles · very rare exomes 1/1,461,870 · genomes 0/152,324 · 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.Val484Ala
Coding: c.1451T>C
MANE Select: NM_001276270
dbSNP: rs1056697984
Type: single nucleotide variant
Location: chr3:129433190 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 490 UniProt numbering: 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); an α-helix

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 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
MBD4 p.Arg181Ter Pathogenic ★★ same condition
MBD4 p.Arg400Ter Pathogenic ★★ same condition
MBD4 p.Arg425Ter Pathogenic ★★ same condition
MBD4 p.Arg540Ter 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-val484ala (accessed [today's date]).

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