Is MBD4 p.Pro28= (c.84A>G) pathogenic?

MBD4 p.Pro28= (c.84A>G) is classified Likely benign in MBD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-01). Ultra-rare (popmax 0.0406%, eas); Associated with Inborn genetic diseases.

What condition is associated with MBD4 p.Pro28= (c.84A>G)?

MBD4 p.Pro28= (c.84A>G) is associated with Inborn genetic diseases (ClinVar).

How common is MBD4 p.Pro28= (c.84A>G) in the general population?

MBD4 p.Pro28= (c.84A>G) is ultra-rare (popmax 0.0406%, eas) (gnomAD).

MBD4 p.Pro28=

c.84A>G · VCV3711346

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0406%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.44	GERP -2.3, phastCons 0.23
Overall
CADD	4.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0406% East Asian · 18/44,298 alleles

Filtering AF 0.0262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0216%

Overall 0.00238% 38/1,597,580 alleles · ultra-rare exomes 36/1,445,414 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0406%	2,461
Remaining individualsnot grpmax-eligible	0.00324%	30,908
European (non-Finnish)	0.00153%	65,149

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.Pro28=
Coding: c.84A>G
MANE Select: NM_001276270
Type: single nucleotide variant
Location: chr3:129439750 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 28: the 'disordered' region

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.Pro28Gln 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
MBD4 p.Arg181Ter Pathogenic ★★ same condition
MBD4 p.Arg400Ter Pathogenic ★★ same condition
MBD4 p.Arg425Ter 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-pro28 (accessed [today's date]).

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