Is MBD5 p.Pro222Ser (c.664C>T) pathogenic?

MBD5 p.Pro222Ser (c.664C>T) is classified Uncertain significance in MBD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-22). AlphaMissense: likely benign (0.15); Very rare (popmax 0.000339%, nfe); Associated with intellectual disability, autosomal dominant 1.

What condition is associated with MBD5 p.Pro222Ser (c.664C>T)?

MBD5 p.Pro222Ser (c.664C>T) is associated with intellectual disability, autosomal dominant 1 (ClinVar).

How common is MBD5 p.Pro222Ser (c.664C>T) in the general population?

MBD5 p.Pro222Ser (c.664C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about MBD5 p.Pro222Ser (c.664C>T)?

AlphaMissense predicts likely benign (score 0.15) — an in-silico prediction, not a clinical call.

MBD5 p.Pro222Ser

c.664C>T · rs772393394 · VCV199154

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.15 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 1

Computational evidence

Protein change
AlphaMissense	0.15	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -5.78	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 4.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 27 kb · p 0.0029 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,896 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,776 alleles · very rare exomes 4/1,461,688 · genomes 1/152,088 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,038
European (non-Finnish)grpmax	0.000339%	294,974

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro222Ser
Coding: c.664C>T
MANE Select: NM_001378120
dbSNP: rs772393394
Type: single nucleotide variant
Location: chr2:148468607 (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.Pro222= Likely benign ★ 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-pro222ser (accessed [today's date]).

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