Is MBD5 p.Pro1717Ser (c.5149C>T) pathogenic?

MBD5 p.Pro1717Ser (c.5149C>T) is classified Uncertain significance in MBD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-09). AlphaMissense: likely benign (0.1312); Very rare (popmax 0.00223%, eas); Associated with intellectual disability, autosomal dominant 1.

What condition is associated with MBD5 p.Pro1717Ser (c.5149C>T)?

MBD5 p.Pro1717Ser (c.5149C>T) is associated with intellectual disability, autosomal dominant 1 (ClinVar).

How common is MBD5 p.Pro1717Ser (c.5149C>T) in the general population?

MBD5 p.Pro1717Ser (c.5149C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MBD5 p.Pro1717Ser (c.5149C>T)?

AlphaMissense predicts likely benign (score 0.1312) — an in-silico prediction, not a clinical call.

MBD5 p.Pro1717Ser

c.5149C>T · rs758847157 · VCV2882226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1312 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 1

Computational evidence

Protein change
AlphaMissense	0.1312	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -5.90	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 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 22 kb · p 0.29 · regional, not allelic
Overall
CADD	23.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1484S vs ClinVar P1717S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,882 alleles

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

Overall 0.000372% 6/1,613,576 alleles · very rare exomes 4/1,461,550 · genomes 2/152,026 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
South Asian	0.0011%	91,066
European (non-Finnish)	0.000339%	294,937

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.Pro1717Ser
Coding: c.5149C>T
MANE Select: NM_001378120
dbSNP: rs758847157
Type: single nucleotide variant
Location: chr2:148512906 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.20
Residue 1484 UniProt numbering: 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.Pro1717= Likely benign ★★ same residue
MBD5 p.Pro1717Thr Uncertain significance ★ ⚠ same residue
MBD5 p.Pro1717Ala 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

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-pro1717ser (accessed [today's date]).

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