Is TMLHE p.Ile321= (c.963C>T) pathogenic?

TMLHE p.Ile321= (c.963C>T) is classified Likely benign in TMLHE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-04). Rare (popmax 0.405%, sas); Associated with TMLHE-related disorder.

What condition is associated with TMLHE p.Ile321= (c.963C>T)?

TMLHE p.Ile321= (c.963C>T) is associated with TMLHE-related disorder (ClinVar).

How common is TMLHE p.Ile321= (c.963C>T) in the general population?

TMLHE p.Ile321= (c.963C>T) is rare (popmax 0.405%, sas) (gnomAD).

TMLHE p.Ile321=

c.963C>T · rs782643746 · VCV3051170

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.405%, sas)

Conditions

TMLHE-related disorder

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 1.4	GERP -0.12, phastCons 1
Overall
CADD	6.726	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.405% South Asian · 230/56,763 alleles

Filtering AF 0.362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.346%

Overall 0.02% 241/1,207,353 alleles · rare exomes 234/1,096,216 · genomes 7/111,137 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.405%	247
Remaining individualsnot grpmax-eligible	0.0105%	9,501
East Asian	0.00297%	33,708
European (non-Finnish)	0.00056%	178,664

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.Ile321=
Coding: c.963C>T
MANE Select: NM_018196
dbSNP: rs782643746
Type: single nucleotide variant
Location: chrX:155506930 (GRCh38)
Structure: AlphaFold pLDDT 89.10

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

Disease context

TMLHE-related disorder

Similar variants

TMLHE p.Ile321fs Pathogenic ★★ same residue
TMLHE p.Thr224Ile Uncertain significance ★ ⚠ same condition
TMLHE p.Arg81Cys Uncertain significance ⚠ same condition
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

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-ile321 (accessed [today's date]).

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