Is MBD5 p.Ser435Phe (c.1304C>T) pathogenic?

MBD5 p.Ser435Phe (c.1304C>T) is classified Conflicting classifications of pathogenicity in MBD5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-23). AlphaMissense: ambiguous (0.54); Ultra-rare (popmax 0.0107%, nfe); Associated with intellectual disability, autosomal dominant 1.

What condition is associated with MBD5 p.Ser435Phe (c.1304C>T)?

MBD5 p.Ser435Phe (c.1304C>T) is associated with intellectual disability, autosomal dominant 1, intellectual disability (ClinVar).

How common is MBD5 p.Ser435Phe (c.1304C>T) in the general population?

MBD5 p.Ser435Phe (c.1304C>T) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

What do computational predictors say about MBD5 p.Ser435Phe (c.1304C>T)?

AlphaMissense predicts ambiguous (score 0.54) — an in-silico prediction, not a clinical call.

MBD5 p.Ser435Phe

c.1304C>T · rs768225923 · VCV468769

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.54 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

Conditions

intellectual disability, autosomal dominant 1

Computational evidence

Protein change
AlphaMissense	0.54	ambiguous
REVEL	0.306	indeterminate
SaProt	LLR -9.27	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 27 kb · p 0.0029 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% European (non-Finnish) · 126/1,179,958 alleles

Filtering AF 0.00911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00855%

Overall 0.00812% 131/1,613,890 alleles · ultra-rare exomes 127/1,461,760 · genomes 4/152,130 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0107%	9,365
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00267%	37,453

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.Ser435Phe
Coding: c.1304C>T
MANE Select: NM_001378120
dbSNP: rs768225923
Type: single nucleotide variant
Location: chr2:148469247 (GRCh38)
Gene constraint: LOEUF 0.161 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.20

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

Also linked: intellectual disability

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-ser435phe (accessed [today's date]).

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