Is MBD4 p.Cys61Arg (c.181T>C) pathogenic?

MBD4 p.Cys61Arg (c.181T>C) is classified Benign/Likely benign in MBD4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-02). AlphaMissense: likely benign (0.111); Rare (popmax 0.16%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MBD4 p.Cys61Arg (c.181T>C)?

MBD4 p.Cys61Arg (c.181T>C) is associated with Inborn genetic diseases, tumor predisposition syndrome 2 (ClinVar).

How common is MBD4 p.Cys61Arg (c.181T>C) in the general population?

MBD4 p.Cys61Arg (c.181T>C) is rare (popmax 0.16%, nfe) (gnomAD).

What do computational predictors say about MBD4 p.Cys61Arg (c.181T>C)?

AlphaMissense predicts likely benign (score 0.111) — an in-silico prediction, not a clinical call.

MBD4 p.Cys61Arg

c.181T>C · rs2307296 · VCV1336002

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.111 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.16%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.111	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -5.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.52	GERP -3.8
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	8.418	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.16% European (non-Finnish) · 1,891/1,179,940 alleles

Filtering AF 0.154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.152%

Overall 0.128% 2,072/1,614,066 alleles · rare exomes 1,830/1,461,792 · genomes 242/152,274 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.16%	624
Finnishnot grpmax-eligible	0.126%	791
Remaining individualsnot grpmax-eligible	0.102%	977
Middle Eastern	0.066%	1,516
Admixed American	0.0233%	4,287
African / African-American	0.0147%	6,821
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
South Asian	0.00329%	30,357

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.Cys61Arg
Coding: c.181T>C
MANE Select: NM_001276270
dbSNP: rs2307296
Type: single nucleotide variant
Location: chr3:129437874 (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

Also linked: tumor predisposition syndrome 2

Similar variants

MBD4 p.Cys61Tyr Uncertain significance ★★ ⚠ same residue
MBD4 c.104+1G>A Likely pathogenic ★★ same condition
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

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-cys61arg (accessed [today's date]).

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