TWSG1

Chr 18

twisted gastrulation BMP signaling modulator 1

Also known as: TSG

NCBI Gene: 57045 ENSG00000128791 UniProt: Q9GZX9 OMIM: 605049

TWSG1 encodes a protein that binds transforming growth factor beta and modulates BMP signaling pathways, which are critical for cartilage development and chondrocyte differentiation. Mutations cause autosomal recessive developmental disorders affecting skeletal and immune system development. The gene shows relatively low constraint to loss-of-function variation.

OMIM ResearchSummary from RefSeq, UniProt

Enables transforming growth factor beta binding activity. Involved in negative regulation of CD4-positive, alpha-beta T cell proliferation; negative regulation of cytokine production; and positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway. Located in centrosome and cytosol. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.03

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.03LOEUF

pLI 0.006

Z-score 1.51

OE 0.49 (0.26–1.03)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.95Z-score

OE missense 0.76 (0.65–0.90)

97 obs / 127.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.26–1.03)

0≤0.351.4

Missense OE?0.76 (0.65–0.90)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 5 / 10.2Missense obs/exp: 97 / 127.2Syn Z: 0.02

Background carrier burden — how many people carry a rare variant somewhere in TWSG1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 360

283 rare PASS variants

Rare truncating (LoF)

1 in 4,500

45 rare PASS variants

Rare synonymous (reference)

1 in 290

102 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TWSG1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 390	1 in 7,600
South Asian	~43k	1 in 180	1 in 1,900
Remaining (unassigned)	~30k	1 in 290	1 in 870
European (Finnish)	~27k	1 in 940	1 in 1,400
Admixed American	~22k	1 in 450	1 in 1,700
African / African American	~21k	1 in 280	≈ 1 in 5,600
East Asian	~20k	1 in 270	1 in 1,600
Ashkenazi Jewish	~13k	1 in 1,900	none seen
Middle Eastern	~2,884	1 in 290	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓