Is TMLHE p.Lys236Ter (c.706A>T) pathogenic?

TMLHE p.Lys236Ter (c.706A>T) is classified Uncertain significance in TMLHE (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). Very rare (popmax 0.00179%, sas).

How common is TMLHE p.Lys236Ter (c.706A>T) in the general population?

TMLHE p.Lys236Ter (c.706A>T) is very rare (popmax 0.00179%, sas) (gnomAD).

TMLHE p.Lys236Ter

c.706A>T · rs782430005 · VCV2690241

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00179%, sas)

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 5 of 8
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.7	GERP 0.71, phastCons 1
Overall
CADD	36.0	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 0.00179% South Asian · 1/55,748 alleles

Overall 8.31e-05% 1/1,203,487 alleles · very rare exomes 1/1,089,875 · genomes 0/113,612 · 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.Lys236Ter
Coding: c.706A>T
MANE Select: NM_018196
dbSNP: rs782430005
Type: single nucleotide variant
Location: chrX:155511725 (GRCh38)
Structure: AlphaFold pLDDT 89.10
Residue 236: a modified residue (n6-acetyllysine)

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

Similar variants

TMLHE p.Lys236fs Uncertain significance ★ same residue
TMLHE p.Arg77Ter Uncertain significance ★★ same type
TMLHE p.Arg93His Uncertain significance ★★ ⚠ same type
TMLHE p.Glu175Lys Uncertain significance ★★ ⚠ same type
TMLHE p.Glu369Asp Uncertain significance ★★ ⚠ same type
TMLHE p.Pro29Ala Uncertain significance ★★ ⚠ same type
TMLHE p.Thr265Ile Uncertain significance ★★ ⚠ same type
TMLHE p.Trp53Ter Uncertain significance ★★ same type

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-lys236ter (accessed [today's date]).

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