ATF6

Chr 1AR

activating transcription factor 6

Also known as: ACHM7, ATF6A, ATP6alpha

NCBI Gene: 22926 ENSG00000118217 UniProt: P18850 OMIM: 605537

ATF6 encodes a transmembrane transcription factor that serves as an endoplasmic reticulum stress sensor and activates the unfolded protein response by translocating to the nucleus to upregulate ER chaperone genes. Biallelic mutations cause achromatopsia 7, an autosomal recessive condition affecting color vision due to cone photoreceptor dysfunction. The gene is moderately constrained against loss-of-function variants (LOEUF 0.698), and comprehensive clinical information is available in GeneReviews.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transcription factor that activates target genes for the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Although it is a transcription factor, this protein is unusual in that it is synthesized as a transmembrane protein that is embedded in the ER. It functions as an ER stress sensor/transducer, and following ER stress-induced proteolysis, it functions as a nuclear transcription factor via a cis-acting ER stress response element (ERSE) that is present in the promoters of genes encoding ER chaperones. This protein has been identified as a survival factor for quiescent but not proliferative squamous carcinoma cells. There have been conflicting reports about the association of polymorphisms in this gene with diabetes in different populations, but another polymorphism has been associated with increased plasma cholesterol levels. This gene is also thought to be a potential therapeutic target for cystic fibrosis. [provided by RefSeq, Aug 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.701 OMIM phenotype

Clinical Summary— ATF6

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Gene-Disease Validity (ClinGen)

ATF6-related retinopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

49 unique Pathogenic / Likely Pathogenic· 248 VUS of 521 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ATF6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.000

Z-score 3.00

OE 0.47 (0.32–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.56Z-score

OE missense 0.92 (0.84–1.00)

323 obs / 352.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.32–0.70)

0≤0.351.4

Missense OE?0.92 (0.84–1.00)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 17 / 36.6Missense obs/exp: 323 / 352.4Syn Z: -0.44

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveATF6-related achromatopsiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7034th %ile

GOF

0.2497th %ile

LOF

0.4430th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

521 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic20

VUS248

Likely Benign172

Benign24

Conflicting4

Pathogenic

Likely Pathogenic

248

VUS

172

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	21	3	5	0	29
Likely Pathogenic	14	4	2	0	20
VUS	5	224	16	3	248
Likely Benign	0	6	73	93	172
Benign	0	7	8	9	24
Conflicting	—				4
Total	40	244	104	105	497

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap ATF6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →