TMLHE p.Leu111=
c.331C>T · rs376662575 · VCV1012899
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
rare (popmax 0.115%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 2.2 | GERP 1.6, phastCons 1 |
| Overall | ||
| CADD | 3.087 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.115%
Middle Eastern · 5/4,335 alleles
Filtering AF
0.0454%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0295%
Overall
0.0143%
172/1,200,823 alleles · rare
exomes 149/1,088,668 · genomes 23/112,155 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.115% | 867 |
| European (non-Finnish) | 0.0174% | 5,746 |
| Remaining individualsnot grpmax-eligible | 0.0127% | 7,868 |
| Finnishnot grpmax-eligible | 0.00862% | 11,604 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00459% | 21,776 |
| Admixed American | 0.00223% | 44,906 |
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.Leu111=
- Coding
- c.331C>T
- MANE Select
- NM_018196
- dbSNP
- rs376662575
- Type
- single nucleotide variant
- Location
- chrX:155524483 (GRCh38)
- Structure
- AlphaFold pLDDT 89.10
Similar variants
- 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
- TMLHE p.Gly266= Likely benign ★★ 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-leu111 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown