Is MBD5 p.Pro222= (c.666C>T) pathogenic?

MBD5 p.Pro222= (c.666C>T) is classified Likely benign in MBD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). Very rare (popmax 6.2e-05%); Associated with intellectual disability, autosomal dominant 1.

What condition is associated with MBD5 p.Pro222= (c.666C>T)?

MBD5 p.Pro222= (c.666C>T) is associated with intellectual disability, autosomal dominant 1 (ClinVar).

How common is MBD5 p.Pro222= (c.666C>T) in the general population?

MBD5 p.Pro222= (c.666C>T) is very rare (popmax 6.2e-05%) (gnomAD).

MBD5 p.Pro222=

c.666C>T · rs1349108004 · VCV1160327

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.68	GERP -0.99, phastCons 0.008
Overall
CADD	7.383	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,613,888 alleles · very rare exomes 1/1,461,694 · genomes 0/152,194 · 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: MBD5
Protein: p.Pro222=
Coding: c.666C>T
MANE Select: NM_001378120
dbSNP: rs1349108004
Type: single nucleotide variant
Location: chr2:148468609 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.20
Residue 222: 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.Pro222Ser Uncertain significance ★★ ⚠ same residue
MBD5 p.Pro222Leu 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

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-pro222 (accessed [today's date]).

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