Is TMLHE p.Ile321fs (c.961_962del) pathogenic?

TMLHE p.Ile321fs (c.961962del) is classified Pathogenic in TMLHE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-05-04). Very rare (popmax 0.00176%, sas); Associated with epsilon-trimethyllysine hydroxylase deficiency.

What condition is associated with TMLHE p.Ile321fs (c.961_962del)?

TMLHE p.Ile321fs (c.961_962del) is associated with epsilon-trimethyllysine hydroxylase deficiency (ClinVar).

How common is TMLHE p.Ile321fs (c.961_962del) in the general population?

TMLHE p.Ile321fs (c.961_962del) is very rare (popmax 0.00176%, sas) (gnomAD).

TMLHE p.Ile321fs

c.961_962del · rs782624357 · VCV225231

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Conditions

epsilon-trimethyllysine hydroxylase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -0.12, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% South Asian · 1/56,923 alleles

Overall 8.27e-05% 1/1,209,172 alleles · very rare exomes 1/1,096,216 · genomes 0/112,956 · joint denominator

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: TMLHE
Protein: p.Ile321fs
Coding: c.961_962del
MANE Select: NM_018196
dbSNP: rs782624357
Type: Microsatellite
Location: chrX:155506931 (GRCh38)
Structure: AlphaFold pLDDT 89.10

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

Disease context

epsilon-trimethyllysine hydroxylase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMLHE p.Ile321= Likely benign same residue
TMLHE p.Arg77Ter Uncertain significance ★★ same condition
TMLHE p.Arg93His Uncertain significance ★★ ⚠ same condition
TMLHE p.Glu175Lys Uncertain significance ★★ ⚠ same condition
TMLHE p.Glu369Asp Uncertain significance ★★ ⚠ same condition
TMLHE p.Thr265Ile Uncertain significance ★★ ⚠ same condition
TMLHE p.Trp53Ter Uncertain significance ★★ same condition
TMLHE p.Trp75Ter 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/tmlhe-p-ile321fs (accessed [today's date]).

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