Is THOC2 p.Ser1108= (c.3324G>A) pathogenic?

THOC2 p.Ser1108= (c.3324G>A) is classified Likely benign in THOC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-26). Very rare (popmax 0.00298%, eas); Associated with X-linked intellectual disability-short stature-overweight syndrome.

What condition is associated with THOC2 p.Ser1108= (c.3324G>A)?

THOC2 p.Ser1108= (c.3324G>A) is associated with X-linked intellectual disability-short stature-overweight syndrome (ClinVar).

How common is THOC2 p.Ser1108= (c.3324G>A) in the general population?

THOC2 p.Ser1108= (c.3324G>A) is very rare (popmax 0.00298%, eas) (gnomAD).

THOC2 p.Ser1108=

c.3324G>A · rs375768878 · VCV1098859

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00298%, eas)

Conditions

X-linked intellectual disability-short stature-overweight syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.055	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9	GERP -5.9
Overall
CADD	0.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00298% East Asian · 1/33,574 alleles

Filtering AF 0.000722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00057%

Overall 0.00109% 13/1,188,569 alleles · very rare exomes 12/1,076,812 · genomes 1/111,757 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00298%	33,574
European (non-Finnish)	0.00135%	73,827

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: THOC2
Protein: p.Ser1108=
Coding: c.3324G>A
MANE Select: NM_001081550
dbSNP: rs375768878
Type: single nucleotide variant
Location: chrX:123623966 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 1108: an α-helix; a UniProt-annotated variant site (in mrxsk; uncertain significance; does not affect nuclear and cytoplasmic localization); the 'stern domain' region

Full THOC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked intellectual disability-short stature-overweight syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

THOC2 p.Ser1108Leu Likely pathogenic ★ same residue
THOC2 p.Cys615Tyr Likely pathogenic ★★ same condition
THOC2 p.Thr696Ile Pathogenic/Likely pathogenic ★★ same condition
THOC2 p.Ala912Pro Uncertain significance ★★ ⚠ same condition
THOC2 p.Asn208Ser Uncertain significance ★★ ⚠ same condition
THOC2 p.Asp656Gly Uncertain significance ★★ ⚠ same condition
THOC2 p.Gly1205Arg Uncertain significance ★★ same condition
THOC2 p.Pro1416Ser Uncertain significance ★★ ⚠ 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/thoc2-p-ser1108 (accessed [today's date]).

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