Is MTM1 p.Arg421Ter (c.1261C>T) pathogenic?

MTM1 p.Arg421Ter (c.1261C>T) is classified Pathogenic in MTM1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2023-09-29). Very rare (popmax 0.000112%, nfe); Associated with neurodevelopmental disorder.

What condition is associated with MTM1 p.Arg421Ter (c.1261C>T)?

MTM1 p.Arg421Ter (c.1261C>T) is associated with neurodevelopmental disorder, X-linked myotubular myopathy, centronuclear myopathy (ClinVar).

How common is MTM1 p.Arg421Ter (c.1261C>T) in the general population?

MTM1 p.Arg421Ter (c.1261C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

MTM1 p.Arg421Ter

c.1261C>T · rs587783771 · VCV158913

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 12 of 15
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP -0.091, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000112% European (non-Finnish) · 1/889,249 alleles

Overall 9.16e-05% 1/1,091,217 alleles · very rare

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: MTM1
Protein: p.Arg421Ter
Coding: c.1261C>T
MANE Select: NM_000252
dbSNP: rs587783771
Type: single nucleotide variant
Location: chrX:150659664 (GRCh38)
Structure: AlphaFold pLDDT 90.10
Residue 421: the myotubularin phosphatase domain; a binding site; a UniProt-annotated variant site (in cnmx; severe; reduced activity and response to pi5p; does not affect interaction with des or mtmr12); a UniProt-annotated variant site (in cnmx; severe)

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

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: X-linked myotubular myopathy centronuclear myopathy

Similar variants

MTM1 p.Arg421Gln Pathogenic/Likely pathogenic ★★ same residue
MTM1 p.Arg421Leu Pathogenic/Likely 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

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-arg421ter (accessed [today's date]).

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