Is TMLHE p.Thr265Ile (c.794C>T) pathogenic?

TMLHE p.Thr265Ile (c.794C>T) is classified Uncertain significance in TMLHE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-28). AlphaMissense: likely benign (0.1762); Very rare (popmax 0.00296%, eas); Associated with epsilon-trimethyllysine hydroxylase deficiency.

What condition is associated with TMLHE p.Thr265Ile (c.794C>T)?

TMLHE p.Thr265Ile (c.794C>T) is associated with epsilon-trimethyllysine hydroxylase deficiency (ClinVar).

How common is TMLHE p.Thr265Ile (c.794C>T) in the general population?

TMLHE p.Thr265Ile (c.794C>T) is very rare (popmax 0.00296%, eas) (gnomAD).

What do computational predictors say about TMLHE p.Thr265Ile (c.794C>T)?

AlphaMissense predicts likely benign (score 0.1762) — an in-silico prediction, not a clinical call.

TMLHE p.Thr265Ile

c.794C>T · rs1557332788 · VCV450888

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epsilon-trimethyllysine hydroxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.1762	likely benign
REVEL	0.691	pathogenic-leaning
SaProt	LLR -8.79	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	24.3	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

Grpmax group 0.00296% East Asian · 1/33,798 alleles

Overall 0.000165% 2/1,208,644 alleles · very rare exomes 2/1,095,648 · genomes 0/112,996 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00296%	33,798
Remaining individualsnot grpmax-eligible	0.0021%	47,512

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.Thr265Ile
Coding: c.794C>T
MANE Select: NM_018196
dbSNP: rs1557332788
Type: single nucleotide variant
Location: chrX:155507099 (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.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.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-thr265ile (accessed [today's date]).

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