Is THOC2 p.Leu438Pro (c.1313T>C) pathogenic?

THOC2 p.Leu438Pro (c.1313T>C) is classified Pathogenic in THOC2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-08-06). AlphaMissense: likely pathogenic (0.9928); No allele count reported in gnomAD v4.1 (AN 1,204,807); Associated with X-linked intellectual disability-short stature-overweight syndrome.

What condition is associated with THOC2 p.Leu438Pro (c.1313T>C)?

THOC2 p.Leu438Pro (c.1313T>C) is associated with X-linked intellectual disability-short stature-overweight syndrome (ClinVar).

How common is THOC2 p.Leu438Pro (c.1313T>C) in the general population?

THOC2 p.Leu438Pro (c.1313T>C) is no allele count reported in gnomAD v4.1 (AN 1,204,807) (gnomAD).

What do computational predictors say about THOC2 p.Leu438Pro (c.1313T>C)?

AlphaMissense predicts likely pathogenic (score 0.9928) — an in-silico prediction, not a clinical call.

THOC2 p.Leu438Pro

c.1313T>C · rs797045018 · VCV208523

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9928 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,204,807)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked intellectual disability-short stature-overweight syndrome

Computational evidence

Protein change
AlphaMissense	0.9928	likely pathogenic ✓ concordant with ClinVar
REVEL	0.73	pathogenic-leaning
SaProt	LLR -15.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 49 kb · p 4.8e-11 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,204,807). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: THOC2
Protein: p.Leu438Pro
Coding: c.1313T>C
MANE Select: NM_001081550
dbSNP: rs797045018
Type: single nucleotide variant
Location: chrX:123665715 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 438: the 'bow domain; interaction with thoc1 dock domain and thoc3' region; a UniProt-annotated variant site (in mrxsk; uncertain significance; reduced amounts of protein; reduced amounts of other tho complex subunits; the mutant protein has a significantly shorter half-life); an α-helix

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.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
THOC2 c.2317-47A>G Benign ★★ 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-leu438pro (accessed [today's date]).

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