Is MBD4 p.Cys61Tyr (c.182G>A) pathogenic?

MBD4 p.Cys61Tyr (c.182G>A) is classified Uncertain significance in MBD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-24). AlphaMissense: likely benign (0.0929); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with MBD4 p.Cys61Tyr (c.182G>A)?

MBD4 p.Cys61Tyr (c.182G>A) is associated with Inborn genetic diseases (ClinVar).

How common is MBD4 p.Cys61Tyr (c.182G>A) in the general population?

MBD4 p.Cys61Tyr (c.182G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MBD4 p.Cys61Tyr (c.182G>A)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

MBD4 p.Cys61Tyr

c.182G>A · VCV3678883

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -7.32	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 0.6	GERP 2.1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	20.6	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

Grpmax group 0.00133% African / African-American · 1/74,932 alleles

Overall 0.000124% 2/1,613,788 alleles · very rare exomes 1/1,461,578 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,932
European (non-Finnish)	8.48e-05%	1,179,782

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.Cys61Tyr
Coding: c.182G>A
MANE Select: NM_001276270
Type: single nucleotide variant
Location: chr3:129437873 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 61: a UniProt-annotated variant site (in)

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.Cys61Arg Benign/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-cys61tyr (accessed [today's date]).

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