Is THOC2 p.Pro1446= (c.4338A>G) pathogenic?

THOC2 p.Pro1446= (c.4338A>G) is classified Benign/Likely benign in THOC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-18). Rare (popmax 0.572%, sas); Associated with X-linked intellectual disability-short stature-overweight syndrome.

What condition is associated with THOC2 p.Pro1446= (c.4338A>G)?

THOC2 p.Pro1446= (c.4338A>G) is associated with X-linked intellectual disability-short stature-overweight syndrome (ClinVar).

How common is THOC2 p.Pro1446= (c.4338A>G) in the general population?

THOC2 p.Pro1446= (c.4338A>G) is rare (popmax 0.572%, sas) (gnomAD).

THOC2 p.Pro1446=

c.4338A>G · rs367878305 · VCV788159

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.572%, sas)

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	0.075	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.1	GERP 2.9, phastCons 1
Overall
CADD	11.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.572% South Asian · 303/53,015 alleles

Filtering AF 0.519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.498%

Overall 0.0288% 343/1,192,603 alleles · rare exomes 332/1,081,584 · genomes 11/111,019 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.572%	175
Remaining individualsnot grpmax-eligible	0.0702%	1,424
Middle Eastern	0.0234%	4,275
African / African-American	0.00177%	56,650
European (non-Finnish)	0.000564%	177,158

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.Pro1446=
Coding: c.4338A>G
MANE Select: NM_001081550
dbSNP: rs367878305
Type: single nucleotide variant
Location: chrX:123614163 (GRCh38)
Structure: AlphaFold pLDDT 72.83 · 4 PDB
Residue 1446: the 'charged domain' region; the 'disordered' 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.Pro1446Ser Uncertain significance ★★ ⚠ 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-pro1446 (accessed [today's date]).

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