Is MBD4 p.Ser574Phe (c.1721C>T) pathogenic?

MBD4 p.Ser574Phe (c.1721C>T) is classified Uncertain significance in MBD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-14). AlphaMissense: ambiguous (0.3753); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with MBD4 p.Ser574Phe (c.1721C>T)?

MBD4 p.Ser574Phe (c.1721C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MBD4 p.Ser574Phe (c.1721C>T) in the general population?

MBD4 p.Ser574Phe (c.1721C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MBD4 p.Ser574Phe (c.1721C>T)?

AlphaMissense predicts ambiguous (score 0.3753) — an in-silico prediction, not a clinical call.

MBD4 p.Ser574Phe

c.1721C>T · VCV3870899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3753	ambiguous
REVEL	0.408	indeterminate
SaProt	LLR -9.72	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S580F vs ClinVar S574F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,010 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,562 alleles · very rare exomes 2/1,460,242 · genomes 0/152,320 · 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.Ser574Phe
Coding: c.1721C>T
MANE Select: NM_001276270
Type: single nucleotide variant
Location: chr3:129431505 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 580 UniProt numbering: 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); a UniProt-annotated variant site (in tpds2 and uvm1); a UniProt-annotated variant site (in uvm1; loss of dna n-glycosylase activity)

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 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
MBD4 p.Arg540Ter Pathogenic/Likely 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-ser574phe (accessed [today's date]).

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