TTR

Chr 18AD

transthyretin

Also known as: AMYLD1, ATTR, CTS, CTS1, HEL111, HsT2651, PALB, TBPA

NCBI Gene: 7276 ENSG00000118271 UniProt: P02766 OMIM: 176300

Transthyretin is a tetrameric carrier protein that transports thyroid hormones in plasma and cerebrospinal fluid and also transports retinol (vitamin A) by associating with retinol-binding protein. Mutations cause autosomal dominant hereditary transthyretin amyloidosis, which predominantly affects peripheral nerves and heart, as well as dystransthyretinemic hyperthyroxinemia and familial carpal tunnel syndrome. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.763), and amyloidosis typically presents in adulthood with progressive polyneuropathy or cardiomyopathy.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

[Dystransthyretinemic hyperthyroxinemia]MIM #145680

Amyloidosis, hereditary systemic 1MIM #105210

Carpal tunnel syndrome, familialMIM #115430

UniProtHyperthyroxinemia, dystransthyretinemic

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · obsolete hereditary ATTR amyloidosis · AD · ClinGen 2017

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

972

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.76

LOEUF

GOF

Mechanism· G2P

📖

GeneReview available — TTR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.76LOEUF

pLI 0.516

Z-score 1.94

OE 0.16 (0.06–0.76)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

1.01Z-score

OE missense 0.69 (0.55–0.86)

57 obs / 83.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.16 (0.06–0.76)

0≤0.351.4

Missense OE?0.69 (0.55–0.86)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 1 / 6.2Missense obs/exp: 57 / 83.0Syn Z: 0.43

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 250

152 rare PASS variants

Rare truncating (LoF)

1 in 9,500

19 rare PASS variants

Rare synonymous (reference)

1 in 830

80 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TTR. 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 530	1 in 18,000
South Asian	~43k	1 in 480	1 in 1,700
Remaining (unassigned)	~30k	1 in 150	≈ 1 in 30,000
European (Finnish)	~27k	1 in 520	none seen
Admixed American	~22k	1 in 200	1 in 1,200
African / African American	~21k	1 in 190	none seen
East Asian	~20k	1 in 380	none seen
Ashkenazi Jewish	~13k	≈ 1 in 3,300	none seen
Middle Eastern	~2,884	1 in 260	none seen

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 ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

TTR · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — TTR

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Amyloidosis, Hereditary

Southeastern ATTR Amyloidosis Consortium: SEATTRAC Family Registry

NOT YET RECRUITING

NCT05974644Virginia Commonwealth UniversityStarted 2026-09

Registry

Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

A Study to Learn About the Use of Acoramidis in Patients With a Heart Condition Called Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in a Real-world Setting

RECRUITING

NCT07235462BayerStarted 2025-10-29

Acoramidis (356 mg film-coated tablets)

ATTRATTR Gene MutationCardiomyopathy

PET/CT Imaging in Carriers of TTR Mutations

NOT YET RECRUITING

NCT07591038University of Texas Southwestern Medical CenterStarted 2026-08-01

Iodine-124 Evuzamitide (I-124E)

CardiomyopathiesAmyloidosis CardiacFabry Disease

Characterization of Patients With Cardiomyopathy to Identify Critical Patients Candidates for Cardiac Transplantation

RECRUITING

NCT06813443IRCCS Azienda Ospedaliero-Universitaria di BolognaStarted 2023-02-13