Is MTM1 p.Val49Phe (c.145G>T) pathogenic?

MTM1 p.Val49Phe (c.145G>T) is classified Pathogenic in MTM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2013-02-08). AlphaMissense: likely pathogenic (0.6843); Absent from gnomAD v4.1; Associated with X-linked myotubular myopathy.

What condition is associated with MTM1 p.Val49Phe (c.145G>T)?

MTM1 p.Val49Phe (c.145G>T) is associated with X-linked myotubular myopathy (ClinVar).

How common is MTM1 p.Val49Phe (c.145G>T) in the general population?

MTM1 p.Val49Phe (c.145G>T) 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.Val49Phe (c.145G>T)?

AlphaMissense predicts likely pathogenic (score 0.6843) — an in-silico prediction, not a clinical call.

MTM1 p.Val49Phe

c.145G>T · rs587783796 · VCV158940

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6843 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked myotubular myopathy

Computational evidence

Protein change
AlphaMissense	0.6843	likely pathogenic ✓ concordant with ClinVar
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.44	acceptor loss · deltas
Pangolin	Δ0.37	loss · gain 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 65 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	25.4	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.Val49Phe
Coding: c.145G>T
MANE Select: NM_000252
dbSNP: rs587783796
Type: single nucleotide variant
Location: chrX:150598600 (GRCh38)
Structure: AlphaFold pLDDT 90.10
Residue 49: the gram domain; a UniProt-annotated variant site (in cnmx; greatly reduced binding to pi(3,5)p2; abolishes interaction with mtmr12; does not translocate to the late endosome following egf stimulation; shows normal egfr degradation)

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.Val49Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MTM1 p.Val49= Likely benign ★ 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

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-val49phe (accessed [today's date]).

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