Is TMLHE p.Trp2Cys (c.6G>T) pathogenic?

TMLHE p.Trp2Cys (c.6G>T) is classified Uncertain significance in TMLHE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-02-05). AlphaMissense: likely benign (0.1807); Very rare (popmax 0.000113%, nfe); Associated with epsilon-trimethyllysine hydroxylase deficiency.

What condition is associated with TMLHE p.Trp2Cys (c.6G>T)?

TMLHE p.Trp2Cys (c.6G>T) is associated with epsilon-trimethyllysine hydroxylase deficiency (ClinVar).

How common is TMLHE p.Trp2Cys (c.6G>T) in the general population?

TMLHE p.Trp2Cys (c.6G>T) is very rare (popmax 0.000113%, nfe) (gnomAD).

What do computational predictors say about TMLHE p.Trp2Cys (c.6G>T)?

AlphaMissense predicts likely benign (score 0.1807) — an in-silico prediction, not a clinical call.

TMLHE p.Trp2Cys

c.6G>T · rs782121512 · VCV828134

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000113%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

epsilon-trimethyllysine hydroxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.1807	likely benign
REVEL	0.419	indeterminate
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP 0.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000113% European (non-Finnish) · 1/885,283 alleles

Overall 8.42e-05% 1/1,187,696 alleles · very rare exomes 1/1,074,398 · genomes 0/113,298 · 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.Trp2Cys
Coding: c.6G>T
MANE Select: NM_018196
dbSNP: rs782121512
Type: single nucleotide variant
Location: chrX:155545271 (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.Trp2Ter Uncertain significance ★ same residue
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 p.Trp75Ter Likely pathogenic ★ 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-trp2cys (accessed [today's date]).

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