Is MBD2 p.Pro157Ala (c.469C>G) pathogenic?

MBD2 p.Pro157Ala (c.469C>G) is classified Uncertain significance in MBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely benign (0.1216); Ultra-rare (popmax 0.0185%, amr).

How common is MBD2 p.Pro157Ala (c.469C>G) in the general population?

MBD2 p.Pro157Ala (c.469C>G) is ultra-rare (popmax 0.0185%, amr) (gnomAD).

What do computational predictors say about MBD2 p.Pro157Ala (c.469C>G)?

AlphaMissense predicts likely benign (score 0.1216) — an in-silico prediction, not a clinical call.

MBD2 p.Pro157Ala

c.469C>G · rs752630383 · VCV2243302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1216 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0185%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1216	likely benign
REVEL	0.4	indeterminate
SaProt	LLR -8.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 487 bp · p 0.032 · regional, not allelic
Overall
CADD	24.8	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 0.0185% Admixed American · 11/59,454 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00802%

Overall 0.00125% 20/1,596,378 alleles · ultra-rare exomes 19/1,444,698 · genomes 1/151,680 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0185%	5,405
Middle Eastern	0.0165%	6,044
East Asian	0.00231%	43,266
Remaining individualsnot grpmax-eligible	0.00161%	62,040
South Asian	0.0011%	90,566
European (non-Finnish)	0.000426%	234,963

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: MBD2
Protein: p.Pro157Ala
Coding: c.469C>G
MANE Select: NM_003927
dbSNP: rs752630383
Type: single nucleotide variant
Location: chr18:54224091 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 68.37 · 14 PDB
Residue 157: the mbd domain; the 'disordered' region

Full MBD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MBD2 p.Pro348= Benign ★★ same type
MBD2 p.Ala172Val Uncertain significance ★ ⚠ same type
MBD2 p.Arg394Gln Uncertain significance ★ ⚠ same type
MBD2 p.Arg86Leu Uncertain significance ★ ⚠ same type
MBD2 p.Arg90Pro Uncertain significance ★ ⚠ same type
MBD2 p.Arg92Gly Uncertain significance ★ ⚠ same type
MBD2 p.Arg94Cys Uncertain significance ★ same type
MBD2 p.Asp107Asn Uncertain significance ★ ⚠ same type

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/mbd2-p-pro157ala (accessed [today's date]).

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