Is MBD4 p.Leu26Val (c.76C>G) pathogenic?

MBD4 p.Leu26Val (c.76C>G) is classified Conflicting classifications of pathogenicity in MBD4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-24). AlphaMissense: likely benign (0.0769); Ultra-rare (popmax 0.0338%, sas); Associated with tumor predisposition syndrome 2.

What condition is associated with MBD4 p.Leu26Val (c.76C>G)?

MBD4 p.Leu26Val (c.76C>G) is associated with tumor predisposition syndrome 2, melanoma, uveal, susceptibility to, 1 (ClinVar).

How common is MBD4 p.Leu26Val (c.76C>G) in the general population?

MBD4 p.Leu26Val (c.76C>G) is ultra-rare (popmax 0.0338%, sas) (gnomAD).

How is MBD4-related tumor predisposition syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MBD4 p.Leu26Val (c.76C>G)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

MBD4 p.Leu26Val

c.76C>G · VCV3543746

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0338%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tumor predisposition syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.95	GERP -1.1, phastCons 0.4
Regional constraint	o/e 0.92	unconstrained · MANE · 8,329 bp · p 0.034 · regional, not allelic
Overall
CADD	13.91	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 0.0338% South Asian · 30/88,860 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00193% 31/1,602,266 alleles · ultra-rare exomes 29/1,450,076 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0338%	2,962
Remaining individualsnot grpmax-eligible	0.00161%	61,954

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.Leu26Val
Coding: c.76C>G
MANE Select: NM_001276270
Type: single nucleotide variant
Location: chr3:129439758 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.67 · 19 PDB
Residue 26: the 'disordered' region

Full MBD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tumor predisposition syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma, uveal, susceptibility to, 1

For MBD4-related tumor predisposition syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

MBD4 p.Leu26Arg Uncertain significance ★★ ⚠ same residue
MBD4 p.Leu26= Likely benign ★★ same residue
MBD4 p.Leu26Gln Uncertain significance ★ ⚠ same residue
MBD4 c.104+1G>A Likely pathogenic ★★ same condition
MBD4 c.1544-1G>T Pathogenic/Likely pathogenic ★★ same condition
MBD4 p.Arg181Ter Pathogenic ★★ same condition
MBD4 p.Gln52Ter Pathogenic ★★ same condition
MBD4 p.Gln73Ter 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-leu26val (accessed [today's date]).

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