Is THOC2 p.Ala912Pro (c.2734G>C) pathogenic?

THOC2 p.Ala912Pro (c.2734G>C) is classified Uncertain significance in THOC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-07). AlphaMissense: likely pathogenic (0.9839); Very rare (popmax 0.000223%, nfe); Associated with X-linked intellectual disability-short stature-overweight syndrome.

What condition is associated with THOC2 p.Ala912Pro (c.2734G>C)?

THOC2 p.Ala912Pro (c.2734G>C) is associated with X-linked intellectual disability-short stature-overweight syndrome (ClinVar).

How common is THOC2 p.Ala912Pro (c.2734G>C) in the general population?

THOC2 p.Ala912Pro (c.2734G>C) is very rare (popmax 0.000223%, nfe) (gnomAD).

What do computational predictors say about THOC2 p.Ala912Pro (c.2734G>C)?

AlphaMissense predicts likely pathogenic (score 0.9839) — an in-silico prediction, not a clinical call.

THOC2 p.Ala912Pro

c.2734G>C · rs1256411821 · VCV1029051

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked intellectual disability-short stature-overweight syndrome

Computational evidence

Protein change
AlphaMissense	0.9839	likely pathogenic
REVEL	0.212	benign-leaning
SaProt	LLR -12.80	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 13 kb · p 1.5e-33 · regional, not allelic
Overall
CADD	26.3	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

Grpmax group 0.000223% European (non-Finnish) · 2/895,061 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000165% 2/1,209,733 alleles · very rare exomes 0/1,097,754 · genomes 2/111,979 · joint denominator

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.Ala912Pro
Coding: c.2734G>C
MANE Select: NM_001081550
dbSNP: rs1256411821
Type: single nucleotide variant
Location: chrX:123627716 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 912: 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.Cys615Tyr Likely pathogenic ★★ same condition
THOC2 p.Thr696Ile Pathogenic/Likely pathogenic ★★ 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
THOC2 c.3058-9C>T 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-ala912pro (accessed [today's date]).

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