Is TMLHE p.Glu175Lys (c.523G>A) pathogenic?

TMLHE p.Glu175Lys (c.523G>A) is classified Uncertain significance in TMLHE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-24). AlphaMissense: likely benign (0.0833); Ultra-rare (popmax 0.046%, mid); Associated with epsilon-trimethyllysine hydroxylase deficiency.

What condition is associated with TMLHE p.Glu175Lys (c.523G>A)?

TMLHE p.Glu175Lys (c.523G>A) is associated with epsilon-trimethyllysine hydroxylase deficiency (ClinVar).

How common is TMLHE p.Glu175Lys (c.523G>A) in the general population?

TMLHE p.Glu175Lys (c.523G>A) is ultra-rare (popmax 0.046%, mid) (gnomAD).

What do computational predictors say about TMLHE p.Glu175Lys (c.523G>A)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

TMLHE p.Glu175Lys

c.523G>A · rs2067136066 · VCV1709697

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.046%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epsilon-trimethyllysine hydroxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -11.13	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP 0.19, phastCons 0.97
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	17.2	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 0.046% Middle Eastern · 2/4,348 alleles

Filtering AF 0.00813% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00341%

Overall 0.000413% 5/1,210,982 alleles · ultra-rare exomes 5/1,097,791 · genomes 0/113,191 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.046%	2,174
East Asian	0.00296%	33,800
South Asian	0.00176%	56,963
European (non-Finnish)	0.000112%	895,111

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.Glu175Lys
Coding: c.523G>A
MANE Select: NM_018196
dbSNP: rs2067136066
Type: single nucleotide variant
Location: chrX:155514101 (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.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
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-glu175lys (accessed [today's date]).

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