Is MBD4 p.Phe393Ser (c.1178T>C) pathogenic?

MBD4 p.Phe393Ser (c.1178T>C) is classified Likely benign in MBD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0743); Very rare (popmax 0.00768%, sas); Associated with Inborn genetic diseases.

What condition is associated with MBD4 p.Phe393Ser (c.1178T>C)?

MBD4 p.Phe393Ser (c.1178T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MBD4 p.Phe393Ser (c.1178T>C) in the general population?

MBD4 p.Phe393Ser (c.1178T>C) is very rare (popmax 0.00768%, sas) (gnomAD).

What do computational predictors say about MBD4 p.Phe393Ser (c.1178T>C)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

MBD4 p.Phe393Ser

c.1178T>C · VCV4052198

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00768%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -4.58	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 1.8	GERP -0.14, phastCons 0.002
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	14.84	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 0.00768% South Asian · 7/91,088 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00062% 10/1,614,018 alleles · very rare exomes 10/1,461,718 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00768%	13,013
East Asian	0.00223%	44,876
European (non-Finnish)	0.000169%	589,991

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.Phe393Ser
Coding: c.1178T>C
MANE Select: NM_001276270
Type: single nucleotide variant
Location: chr3:129436466 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 393: 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.Phe393Ile Uncertain significance ★★ ⚠ same residue
MBD4 p.Phe393Val Uncertain significance ★★ ⚠ same residue
MBD4 p.Phe393Leu 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
MBD4 c.335+1G>A Likely pathogenic ★★ same condition
MBD4 p.Arg181Ter 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-phe393ser (accessed [today's date]).

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