Is MBD5 p.Pro338Ser (c.1012C>T) pathogenic?

MBD5 p.Pro338Ser (c.1012C>T) is classified Uncertain significance in MBD5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-23). AlphaMissense: likely benign (0.1324); Very rare (popmax 0.00267%, afr); Associated with intellectual disability, autosomal dominant 1.

What condition is associated with MBD5 p.Pro338Ser (c.1012C>T)?

MBD5 p.Pro338Ser (c.1012C>T) is associated with intellectual disability, autosomal dominant 1 (ClinVar).

How common is MBD5 p.Pro338Ser (c.1012C>T) in the general population?

MBD5 p.Pro338Ser (c.1012C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MBD5 p.Pro338Ser (c.1012C>T)?

AlphaMissense predicts likely benign (score 0.1324) — an in-silico prediction, not a clinical call.

MBD5 p.Pro338Ser

c.1012C>T · rs755505551 · VCV1486301

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1324 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 1

Computational evidence

Protein change
AlphaMissense	0.1324	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 27 kb · p 0.0029 · regional, not allelic
Overall
CADD	25.1	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 0.00267% African / African-American · 2/74,822 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,486 alleles · very rare exomes 0/1,461,556 · genomes 2/151,930 · 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.Pro338Ser
Coding: c.1012C>T
MANE Select: NM_001378120
dbSNP: rs755505551
Type: single nucleotide variant
Location: chr2:148468955 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.20
Residue 338: 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 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
MBD5 p.Gln813Ter Pathogenic/Likely 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-pro338ser (accessed [today's date]).

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