Is TMLHE p.Glu369Asp (c.1107G>T) pathogenic?

TMLHE p.Glu369Asp (c.1107G>T) is classified Uncertain significance in TMLHE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-08). AlphaMissense: likely pathogenic (0.9211); Absent from gnomAD v4.1; Associated with epsilon-trimethyllysine hydroxylase deficiency.

What condition is associated with TMLHE p.Glu369Asp (c.1107G>T)?

TMLHE p.Glu369Asp (c.1107G>T) is associated with epsilon-trimethyllysine hydroxylase deficiency (ClinVar).

How common is TMLHE p.Glu369Asp (c.1107G>T) in the general population?

TMLHE p.Glu369Asp (c.1107G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMLHE p.Glu369Asp (c.1107G>T)?

AlphaMissense predicts likely pathogenic (score 0.9211) — an in-silico prediction, not a clinical call.

TMLHE p.Glu369Asp

c.1107G>T · rs782001959 · VCV225230

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9211 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epsilon-trimethyllysine hydroxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.9211	likely pathogenic
REVEL	0.651	pathogenic-leaning
SaProt	LLR -11.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.14	phastCons 0.7
Regional constraint	o/e 0.43	unconstrained · MANE · 15 kb · p 0.00014 · regional, not allelic
Overall
CADD	19.27	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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: TMLHE
Protein: p.Glu369Asp
Coding: c.1107G>T
MANE Select: NM_018196
dbSNP: rs782001959
Type: single nucleotide variant
Location: chrX:155492384 (GRCh38)
Structure: AlphaFold pLDDT 89.10
Residue 369: a UniProt-annotated variant site (in autsx6; uncertain significance)

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.Arg77Ter Uncertain significance ★★ same condition
TMLHE p.Arg93His Uncertain significance ★★ ⚠ same condition
TMLHE p.Glu175Lys 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
TMLHE c.359-2A>G Conflicting classifications of pathogenicity ★ same condition
TMLHE c.995+2T>C 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-glu369asp (accessed [today's date]).

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