# NM_007348.4(ATF6):c.435G>A (p.Ala145=)

https://sugi.bio/variant/atf6-p-ala145

## Summary

**ATF6 p.Ala145= (c.435G>A)** is classified **Uncertain significance** in ATF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). Ultra-rare (popmax 0.0173%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs570613028 · 1 submitter · ultra-rare (popmax 0.0173%, afr)

## For patients & families {#patients}

This is a change in the ATF6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ATF6](https://sugi.bio/atlas/gene/ATF6/) |
| Protein change (HGVS p.) | p.Ala145= |
| Coding change (HGVS c.) | c.435G>A |
| MANE Select transcript | [NM_007348](https://www.ncbi.nlm.nih.gov/nuccore/NM_007348) |
| dbSNP | [rs570613028](https://www.ncbi.nlm.nih.gov/snp/rs570613028/) |
| Variant type | single nucleotide variant |
| Location | chr1:161791488-161791488 (GRCh38) |
| ClinVar | [VCV970223](https://www.ncbi.nlm.nih.gov/clinvar/variation/970223/) |

**All HGVS expressions:** `NC_000001.10:g.161761278G>A`, `NC_000001.11:g.161791488G>A`, `NG_029773.1:g.30245G>A`, `NM_007348.4:c.435G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.365, GERP -2.05, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 6.49**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.01**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.01**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0173%** (afr) · FAF95 0.0102% · FAF99 0.00813% · 13/74,938 in the highest group · 27/1,612,488 alleles overall — ultra-rare (popmax 0.0173%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0173% | 5,764 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,230 |
| South Asian | 0.0022% | 45,512 |
| Admixed American | 0.00167% | 59,896 |
| European (non-Finnish) | 0.000763% | 131,065 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ATF6** population constraint: LOEUF 0.882, pLI 1.6011e-07, missense-Z 0.76705; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ATF6-related retinopathy** — Definitive (AR)

## Protein context {#protein}

Residue **145** lies in a UniProt-annotated variant site (in); the 'transcription activation' region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 56.09, 15% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ATF6 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ATF6's established molecular role includes transcription cis-regulatory region binding. p.Ala145= falls in the transcription activation region.


### Pathways affected {#pathways}

ATF6 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ATF6 (ATF6-alpha) activates chaperones](https://reactome.org/content/detail/R-HSA-381033) | curated |
| [Modulation of host responses by IFN-stimulated genes](https://reactome.org/content/detail/R-HSA-9909505) | curated |
| [ATF4 activates genes in response to endoplasmic reticulum  stress](https://reactome.org/content/detail/R-HSA-380994) | electronic |
| [ATF6 (ATF6-alpha) activates chaperone genes](https://reactome.org/content/detail/R-HSA-381183) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II transcription regulatory region sequence-specific DNA binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity, enzyme binding.

**Biological process:** eye development, visual perception, positive regulation of autophagy, response to endoplasmic reticulum stress, positive regulation of apoptotic process, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-24.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-24 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ATF6 variant pages (same residue, condition, or type): [ATF6 p.Ala145Pro](/variant/atf6-p-ala145pro), [ATF6 p.Ala145Glu](/variant/atf6-p-ala145glu), [ATF6 p.Ala145Val](/variant/atf6-p-ala145val), [ATF6 c.1533+1G>C](/variant/atf6-c-1533-plus-1g-c), [ATF6 c.160-1G>A](/variant/atf6-c-160-minus-1g-a), [ATF6 c.484+1G>A](/variant/atf6-c-484-plus-1g-a), [ATF6 c.484+1G>T](/variant/atf6-c-484-plus-1g-t), [ATF6 c.82+5G>T](/variant/atf6-c-82-plus-5g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 970223). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*