Is MBD2 p.Pro122Ser (c.364C>T) pathogenic?

MBD2 p.Pro122Ser (c.364C>T) is classified Uncertain significance in MBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely benign (0.0731); Very rare (popmax 0.00402%, sas).

How common is MBD2 p.Pro122Ser (c.364C>T) in the general population?

MBD2 p.Pro122Ser (c.364C>T) is very rare (popmax 0.00402%, sas) (gnomAD).

What do computational predictors say about MBD2 p.Pro122Ser (c.364C>T)?

AlphaMissense predicts likely benign (score 0.0731) — an in-silico prediction, not a clinical call.

MBD2 p.Pro122Ser

c.364C>T · VCV4550197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0731	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -6.67	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 7.3	GERP -0.82, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 487 bp · p 0.032 · regional, not allelic
Overall
CADD	23.5	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 0.00402% South Asian · 1/24,872 alleles

Filtering AF 8.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.3e-05%

Overall 0.000414% 5/1,208,898 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00402%	24,872
Remaining individualsnot grpmax-eligible	0.00227%	44,034
European (non-Finnish)	0.000308%	324,904

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.Pro122Ser
Coding: c.364C>T
MANE Select: NM_003927
Type: single nucleotide variant
Location: chr18:54224196 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 68.37 · 14 PDB
Residue 122: the 'disordered' region; the 'required for interaction with dhx9 and prmt5' 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-pro122ser (accessed [today's date]).

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