Is MBD4 p.Ser422= (c.1266C>T) pathogenic?

MBD4 p.Ser422= (c.1266C>T) is classified Benign/Likely benign in MBD4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-11). Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with MBD4 p.Ser422= (c.1266C>T)?

MBD4 p.Ser422= (c.1266C>T) is associated with Inborn genetic diseases, tumor predisposition syndrome 2 (ClinVar).

How common is MBD4 p.Ser422= (c.1266C>T) in the general population?

MBD4 p.Ser422= (c.1266C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

MBD4 p.Ser422=

c.1266C>T · rs758935058 · VCV2783195

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

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	all four deltas below 0.2 · G>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.6	GERP -2.4, phastCons 0.99
Overall
CADD	7.087	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,010 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,080 alleles · very rare exomes 1/1,461,850 · genomes 1/152,230 · 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.Ser422=
Coding: c.1266C>T
MANE Select: NM_001276270
dbSNP: rs758935058
Type: single nucleotide variant
Location: chr3:129433977 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 422: 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

Also linked: tumor predisposition syndrome 2

Similar variants

MBD4 p.Ser422Arg 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-ser422 (accessed [today's date]).

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