Is TMLHE p.Trp75Ter (c.224G>A) pathogenic?

TMLHE p.Trp75Ter (c.224G>A) is classified Likely pathogenic in TMLHE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). Very rare (popmax 0.00367%, sas); Associated with epsilon-trimethyllysine hydroxylase deficiency.

What condition is associated with TMLHE p.Trp75Ter (c.224G>A)?

TMLHE p.Trp75Ter (c.224G>A) is associated with epsilon-trimethyllysine hydroxylase deficiency (ClinVar).

How common is TMLHE p.Trp75Ter (c.224G>A) in the general population?

TMLHE p.Trp75Ter (c.224G>A) is very rare (popmax 0.00367%, sas) (gnomAD).

TMLHE p.Trp75Ter

c.224G>A · VCV4845897

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00367%, sas)

Conditions

epsilon-trimethyllysine hydroxylase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 8
Splicing
SpliceAI	Δ0.89	acceptor gain · deltas
Pangolin	Δ0.39	gain · loss 0.16 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.2	GERP 3.4, phastCons 1
Overall
CADD	44.0	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 0.00367% South Asian · 2/54,551 alleles

Filtering AF 0.000608% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000228%

Overall 0.000166% 2/1,202,343 alleles · very rare exomes 2/1,088,898 · genomes 0/113,445 · 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.Trp75Ter
Coding: c.224G>A
MANE Select: NM_018196
Type: single nucleotide variant
Location: chrX:155524590 (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.Thr265Ile Uncertain significance ★★ ⚠ same condition
TMLHE p.Trp53Ter Uncertain significance ★★ 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-trp75ter (accessed [today's date]).

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