Is THOC6 p.Leu289= (c.865C>T) pathogenic?

THOC6 p.Leu289= (c.865C>T) is classified Likely benign in THOC6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-12). Ultra-rare (popmax 0.0275%, nfe); Associated with THOC6-related disorder.

What condition is associated with THOC6 p.Leu289= (c.865C>T)?

THOC6 p.Leu289= (c.865C>T) is associated with THOC6-related disorder (ClinVar).

How common is THOC6 p.Leu289= (c.865C>T) in the general population?

THOC6 p.Leu289= (c.865C>T) is ultra-rare (popmax 0.0275%, nfe) (gnomAD).

THOC6 p.Leu289=

c.865C>T · rs144446793 · VCV3035559

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0275%, nfe)

Conditions

THOC6-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 5.9	GERP 1.3, phastCons 1
Overall
CADD	12.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0275% European (non-Finnish) · 324/1,179,590 alleles

Filtering AF 0.0249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.0215% 346/1,612,214 alleles · ultra-rare exomes 329/1,459,928 · genomes 17/152,286 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.032%	3,122
European (non-Finnish)grpmax	0.0275%	3,641
African / African-American	0.00267%	37,477

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: THOC6
Protein: p.Leu289=
Coding: c.865C>T
MANE Select: NM_024339
dbSNP: rs144446793
Type: single nucleotide variant
Location: chr16:3027420 (GRCh38)
Gene constraint: LOEUF 0.872 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.63 · 3 PDB
Residue 289: a β-strand

Full THOC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

THOC6-related disorder

Similar variants

THOC6 c.155+1G>T Pathogenic/Likely pathogenic ★★ same condition
THOC6 p.Gly190Glu Pathogenic/Likely pathogenic ★★ same condition
THOC6 p.Gly46Arg Likely pathogenic ★★ same condition
THOC6 p.Arg193Ter Likely pathogenic ★ same condition
THOC6 p.Tyr170Ter Likely pathogenic ★ same condition
THOC6 p.Ala310= Likely benign same condition
THOC6 p.Val79= Likely benign same condition
THOC6 p.Arg115fs Pathogenic/Likely pathogenic ★★ 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/thoc6-p-leu289 (accessed [today's date]).

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