TFF1

Chr 21

trefoil factor 1

Also known as: BCEI, D21S21, HP1.A, HPS2, pNR-2, pS2

TFF1 encodes a secretory protein that stabilizes the mucous gel overlying the gastrointestinal mucosa, providing a physical barrier against noxious agents and may inhibit calcium oxalate crystal growth in urine. The gene is not highly constrained against loss-of-function variants, and no established Mendelian disorders have been definitively linked to TFF1 mutations in current databases.

Summary from RefSeq, UniProt

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Active trials

Pubs (1 yr)

P/LP submissions

—

P/LP missense

1.91

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— TFF1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Some data sources returned errors (2)

ensembl: TimeoutError: The operation was aborted due to timeout

pubtator: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

1.91LOEUF

pLI 0.001

Z-score -0.45

OE 1.28 (0.58–1.91)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint

-0.13Z-score

OE missense 1.05 (0.85–1.31)

57 obs / 54.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE1.28 (0.58–1.91)

0≤0.351.4

Missense OE1.05 (0.85–1.31)

0≤0.61.4

Synonymous OE1.06

0≤1.21.6

LoF obs/exp: 4 / 3.1Missense obs/exp: 57 / 54.2Syn Z: -0.24

0.6937th %ile

GOF

0.77top 25%

LOF

0.1598th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.