Is MBD5 p.Ala225= (c.675G>A) pathogenic?

MBD5 p.Ala225= (c.675G>A) is classified Likely benign in MBD5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Very rare (popmax 0.00891%, eas); Associated with intellectual disability, autosomal dominant 1.

What condition is associated with MBD5 p.Ala225= (c.675G>A)?

MBD5 p.Ala225= (c.675G>A) is associated with intellectual disability, autosomal dominant 1 (ClinVar).

How common is MBD5 p.Ala225= (c.675G>A) in the general population?

MBD5 p.Ala225= (c.675G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

MBD5 p.Ala225=

c.675G>A · rs775582219 · VCV261023

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Conditions

intellectual disability, autosomal dominant 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.8	GERP -4.8
Overall
CADD	1.626	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,870 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00291% 47/1,613,748 alleles · very rare exomes 44/1,461,698 · genomes 3/152,050 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
Admixed American	0.00834%	11,994
European (non-Finnish)	0.00314%	31,888
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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: MBD5
Protein: p.Ala225=
Coding: c.675G>A
MANE Select: NM_001378120
dbSNP: rs775582219
Type: single nucleotide variant
Location: chr2:148468618 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.20
Residue 225: the 'disordered' region

Full MBD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal dominant 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MBD5 p.Ala225Val Uncertain significance ★ ⚠ same residue
MBD5 c.397+1G>A Pathogenic ★★ same condition
MBD5 c.397+2T>C Pathogenic ★★ same condition
MBD5 p.Arg1440Ter Pathogenic ★★ same condition
MBD5 p.Arg200Ter Pathogenic ★★ same condition
MBD5 p.Arg325Ter Pathogenic/Likely pathogenic ★★ same condition
MBD5 p.Cys60Ter Pathogenic ★★ same condition
MBD5 p.Gln587Ter 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/mbd5-p-ala225 (accessed [today's date]).

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