Is TMLHE p.Arg93His (c.278G>A) pathogenic?

TMLHE p.Arg93His (c.278G>A) is classified Uncertain significance in TMLHE (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-07-30). AlphaMissense: likely pathogenic (0.8279); Ultra-rare (popmax 0.0687%, mid); Associated with epsilon-trimethyllysine hydroxylase deficiency.

What condition is associated with TMLHE p.Arg93His (c.278G>A)?

TMLHE p.Arg93His (c.278G>A) is associated with epsilon-trimethyllysine hydroxylase deficiency (ClinVar).

How common is TMLHE p.Arg93His (c.278G>A) in the general population?

TMLHE p.Arg93His (c.278G>A) is ultra-rare (popmax 0.0687%, mid) (gnomAD).

What do computational predictors say about TMLHE p.Arg93His (c.278G>A)?

AlphaMissense predicts likely pathogenic (score 0.8279) — an in-silico prediction, not a clinical call.

TMLHE p.Arg93His

c.278G>A · rs145371120 · VCV982862

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8279 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0687%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

epsilon-trimethyllysine hydroxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.8279	likely pathogenic
REVEL	0.598	indeterminate
SaProt	LLR -13.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	23.0	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

Grpmax group 0.0687% Middle Eastern · 3/4,365 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.0217% 262/1,207,866 alleles · ultra-rare exomes 245/1,095,771 · genomes 17/112,095 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0687%	1,455
European (non-Finnish)	0.0262%	3,821
African / African-American	0.0245%	4,083
Remaining individualsnot grpmax-eligible	0.0126%	7,916
South Asian	0.00712%	14,044
East Asian	0.00297%	33,696

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.Arg93His
Coding: c.278G>A
MANE Select: NM_018196
dbSNP: rs145371120
Type: single nucleotide variant
Location: chrX:155524536 (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.Arg93Cys Uncertain significance ★ ⚠ same residue
TMLHE p.Arg77Ter 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
TMLHE c.359-2A>G Conflicting classifications of pathogenicity ★ 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-arg93his (accessed [today's date]).

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