Is MBD4 p.Pro424Arg (c.1271C>G) pathogenic?

MBD4 p.Pro424Arg (c.1271C>G) is classified Uncertain significance in MBD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-11). AlphaMissense: likely pathogenic (0.8199); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with MBD4 p.Pro424Arg (c.1271C>G)?

MBD4 p.Pro424Arg (c.1271C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MBD4 p.Pro424Arg (c.1271C>G) in the general population?

MBD4 p.Pro424Arg (c.1271C>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about MBD4 p.Pro424Arg (c.1271C>G)?

AlphaMissense predicts likely pathogenic (score 0.8199) — an in-silico prediction, not a clinical call.

MBD4 p.Pro424Arg

c.1271C>G · rs772947874 · VCV2549415

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8199	likely pathogenic
REVEL	0.72	pathogenic-leaning
SaProt	LLR -13.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.24	acceptor gain, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 P430R vs ClinVar P424R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,614,156 alleles · very rare exomes 3/1,461,862 · genomes 0/152,294 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,540
European (non-Finnish)	8.47e-05%	1,180,006

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.Pro424Arg
Coding: c.1271C>G
MANE Select: NM_001276270
dbSNP: rs772947874
Type: single nucleotide variant
Location: chr3:129433972 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 430 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)

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.Pro424Gln Uncertain significance ★★ ⚠ same residue
MBD4 p.Pro424= Benign/Likely benign ★★ same residue
MBD4 p.Pro424Ala Uncertain significance ★ same residue
MBD4 p.Pro424fs Pathogenic ★ same residue
MBD4 p.Pro424Leu Uncertain significance ★ ⚠ 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

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-pro424arg (accessed [today's date]).

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