Is TMLHE p.Arg77Ter (c.229C>T) pathogenic?

TMLHE p.Arg77Ter (c.229C>T) is classified Uncertain significance in TMLHE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2020-09-10). Ultra-rare (popmax 0.0266%, amr); Associated with intellectual disability.

What condition is associated with TMLHE p.Arg77Ter (c.229C>T)?

TMLHE p.Arg77Ter (c.229C>T) is associated with intellectual disability, epsilon-trimethyllysine hydroxylase deficiency (ClinVar).

How common is TMLHE p.Arg77Ter (c.229C>T) in the general population?

TMLHE p.Arg77Ter (c.229C>T) is ultra-rare (popmax 0.0266%, amr) (gnomAD).

TMLHE p.Arg77Ter

c.229C>T · rs781889971 · VCV225228

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0266%, amr)

Conditions

intellectual disability

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 8
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.6, phastCons 1
Overall
CADD	35.0	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 0.0266% Admixed American · 12/45,119 alleles

Filtering AF 0.0153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00932% 112/1,202,187 alleles · ultra-rare exomes 106/1,090,147 · genomes 6/112,040 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0266%	3,760
Remaining individualsnot grpmax-eligible	0.0148%	6,755
European (non-Finnish)	0.0103%	9,688
African / African-American	0.00175%	57,034

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.Arg77Ter
Coding: c.229C>T
MANE Select: NM_018196
dbSNP: rs781889971
Type: single nucleotide variant
Location: chrX:155524585 (GRCh38)
Structure: AlphaFold pLDDT 89.10

Full TMLHE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epsilon-trimethyllysine hydroxylase deficiency

Similar variants

TMLHE p.Arg77Gln Uncertain significance ★ ⚠ same residue
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
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-arg77ter (accessed [today's date]).

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