Is THOC2 p.Ala648Ser (c.1942G>T) pathogenic?

THOC2 p.Ala648Ser (c.1942G>T) is classified Likely pathogenic in THOC2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.1099); Absent from gnomAD v4.1; Associated with X-linked intellectual disability-short stature-overweight syndrome.

What condition is associated with THOC2 p.Ala648Ser (c.1942G>T)?

THOC2 p.Ala648Ser (c.1942G>T) is associated with X-linked intellectual disability-short stature-overweight syndrome (ClinVar).

How common is THOC2 p.Ala648Ser (c.1942G>T) in the general population?

THOC2 p.Ala648Ser (c.1942G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THOC2 p.Ala648Ser (c.1942G>T)?

AlphaMissense predicts likely benign (score 0.1099) — an in-silico prediction, not a clinical call.

THOC2 p.Ala648Ser

c.1942G>T · rs2047665750 · VCV982367

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1099 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

X-linked intellectual disability-short stature-overweight syndrome

Computational evidence

Protein change
AlphaMissense	0.1099	likely benign ⚠ discordant with ClinVar
REVEL	0.422	indeterminate
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 13 kb · p 1.5e-33 · regional, not allelic
Overall
CADD	23.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: THOC2
Protein: p.Ala648Ser
Coding: c.1942G>T
MANE Select: NM_001081550
dbSNP: rs2047665750
Type: single nucleotide variant
Location: chrX:123636155 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 648: the 'mif4g domain; interaction with thoc3 and ddx39b' region; 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-ala648ser (accessed [today's date]).

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