Is TMLHE p.Lys236fs (c.705del) pathogenic?

TMLHE p.Lys236fs (c.705del) is classified Uncertain significance in TMLHE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-20). Very rare (popmax 0.000112%, nfe); Associated with epsilon-trimethyllysine hydroxylase deficiency.

What condition is associated with TMLHE p.Lys236fs (c.705del)?

TMLHE p.Lys236fs (c.705del) is associated with epsilon-trimethyllysine hydroxylase deficiency (ClinVar).

How common is TMLHE p.Lys236fs (c.705del) in the general population?

TMLHE p.Lys236fs (c.705del) is very rare (popmax 0.000112%, nfe) (gnomAD).

TMLHE p.Lys236fs

c.705del · VCV4883893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

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 5 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.7	GERP 0.71, phastCons 1
Overall
CADD	22.9	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) · 1/889,550 alleles

Overall 8.32e-05% 1/1,201,612 alleles · very rare exomes 0/1,089,875 · genomes 1/111,737 · 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.Lys236fs
Coding: c.705del
MANE Select: NM_018196
Type: Deletion
Location: chrX:155511726 (GRCh38)
Structure: AlphaFold pLDDT 89.10
Residue 236: a modified residue (n6-acetyllysine)

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 c.638+83_995+2127del Uncertain significance ★ same condition
TMLHE p.Lys236Ter Uncertain significance ★ same residue
TMLHE c.638+2del Likely pathogenic same condition
TMLHE c.639-10_758+10del Uncertain significance same condition
TMLHE p.Ile321fs Pathogenic ★★ same condition
TMLHE p.Arg77Ter Uncertain significance ★★ same condition
TMLHE p.Arg93His Uncertain significance ★★ ⚠ same condition
TMLHE p.Glu175Lys Uncertain significance ★★ ⚠ 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-lys236fs (accessed [today's date]).

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