TXNDC12

Chr 1

thioredoxin domain containing 12

Also known as: AG1, AGR1, ERP16, ERP18, ERP19, PDIA16, TLP19, hAG-1

NCBI Gene: 51060 ENSG00000117862 UniProt: O95881

This endoplasmic reticulum protein functions as a protein-disulfide reductase that promotes disulfide bond formation in client proteins and may protect against ER stress. Mutations cause autosomal recessive developmental and epileptic encephalopathy with severe intellectual disability and seizures beginning in infancy. The gene shows low constraint to loss-of-function variants, consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the thioredoxin superfamily. Members of this family are characterized by a conserved active motif called the thioredoxin fold that catalyzes disulfide bond formation and isomerization. This protein localizes to the endoplasmic reticulum and has a single atypical active motif. The encoded protein is mainly involved in catalyzing native disulfide bond formation and displays activity similar to protein-disulfide isomerases. This protein may play a role in defense against endoplasmic reticulum stress. Alternate splicing results in both coding and non-coding variants. [provided by RefSeq, Mar 2012]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.33

Clinical Summary— TXNDC12

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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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ClinVar Variants

67 VUS of 82 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.33LOEUF

pLI 0.000

Z-score 0.80

OE 0.74 (0.43–1.33)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.52Z-score

OE missense 0.85 (0.71–1.02)

78 obs / 92.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.43–1.33)

0≤0.351.4

Missense OE?0.85 (0.71–1.02)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 8 / 10.8Missense obs/exp: 78 / 92.0Syn Z: 0.66

This gene — mechanism propensity

0.6454th %ile

GOF

0.6345th %ile

LOF

0.3067th %ile

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

DNprediction above median

GOFprediction 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.

ClinVar Variant Classifications

82 submitted variants in ClinVar

ClinVar

Classification Summary

VUS67

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	67	67
Likely Benign	2	2
Benign	0	0
Total	69	69

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

8 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap TXNDC12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →