Is MTM1 p.Phe478Ser (c.1433T>C) pathogenic?

MTM1 p.Phe478Ser (c.1433T>C) is classified Pathogenic in MTM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2013-02-08). AlphaMissense: likely pathogenic (0.9936); Absent from gnomAD v4.1; Associated with X-linked myotubular myopathy.

What condition is associated with MTM1 p.Phe478Ser (c.1433T>C)?

MTM1 p.Phe478Ser (c.1433T>C) is associated with X-linked myotubular myopathy (ClinVar).

How common is MTM1 p.Phe478Ser (c.1433T>C) in the general population?

MTM1 p.Phe478Ser (c.1433T>C) is absent from gnomAD v4.1 (gnomAD).

How is X-linked centronuclear myopathy inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MTM1 p.Phe478Ser (c.1433T>C)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

MTM1 p.Phe478Ser

c.1433T>C · rs587783794 · VCV158937

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked myotubular myopathy

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic ✓ concordant with ClinVar · top 9% in MTM1
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -15.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 5,629 bp · p 2.6e-06 · regional, not allelic
Overall
CADD	29.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MTM1
Protein: p.Phe478Ser
Coding: c.1433T>C
MANE Select: NM_000252
dbSNP: rs587783794
Type: single nucleotide variant
Location: chrX:150660450 (GRCh38)
Structure: AlphaFold pLDDT 90.10
Residue 478: the myotubularin phosphatase domain

Full MTM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked myotubular myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked centronuclear myopathy (Orphanet):

Inheritance: X-linked recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (France)

Similar variants

MTM1 p.Phe478_Leu479insPhePhePhePhePhePhePheXaaXaaXaaXaaSerSerAlaSerLeuThrLeuGlyAlaValAspArgSerCysSerTyrSerAlaIleLeuAlaProProProGlyThrPhe Pathogenic ★ same residue
MTM1 c.1644+1G>A Pathogenic ★★★ same condition
MTM1 p.Arg224Ter Pathogenic ★★★ same condition
MTM1 p.Arg69Cys Pathogenic ★★★ same condition
MTM1 p.Gln451= Likely pathogenic ★★★ same condition
MTM1 p.Glu404Lys Pathogenic ★★★ same condition
MTM1 p.Pro205Leu Pathogenic ★★★ same condition
MTM1 p.Trp230Arg 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/mtm1-p-phe478ser (accessed [today's date]).

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