# NM_182810.3(ATF4):c.772C>G (p.Pro258Ala)

https://sugi.bio/variant/atf4-p-pro258ala

## Summary

**ATF4 p.Pro258Ala (c.772C>G)** is classified **Benign** in ATF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0891); Low-frequency (popmax 4.6%, afr).

**At a glance:** Benign · review: Multiple submitters · rsID rs1803323 · 2 submitters · AlphaMissense likely benign · low-frequency (popmax 4.6%, afr)

## For patients & families {#patients}

This is a change in the ATF4 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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 | [ATF4](https://sugi.bio/atlas/gene/ATF4/) |
| Protein change (HGVS p.) | p.Pro258Ala |
| Coding change (HGVS c.) | c.772C>G |
| MANE Select transcript | [NM_182810](https://www.ncbi.nlm.nih.gov/nuccore/NM_182810) |
| dbSNP | [rs1803323](https://www.ncbi.nlm.nih.gov/snp/rs1803323/) |
| Variant type | single nucleotide variant |
| Location | chr22:39522318-39522318 (GRCh38) |
| ClinVar | [VCV780657](https://www.ncbi.nlm.nih.gov/clinvar/variation/780657/) |

**All HGVS expressions:** `NC_000022.10:g.39918323C>G`, `NC_000022.11:g.39522318C>G`, `NM_001675.4:c.772C>G`, `NM_182810.3:c.772C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0891)
- REVEL 0.049 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.139 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.205, GERP -1.58, phastCons 0.974 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.7**. 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.*
- Regional missense constraint: **o/e 1.29** across the covering region of the MANE Select transcript (39,521,446–39,522,599), spanning 1,153 bp. Chi-square p 2.5e-09. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **4.6%** (afr) · FAF95 4.48% · FAF99 4.42% · 3,448/74,902 in the highest group · 3,843/1,612,688 alleles overall — low-frequency (popmax 4.6%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 4.6% | 22 |
| Remaining individuals (not grpmax-eligible) | 0.291% | 343 |
| Admixed American | 0.254% | 393 |
| Middle Eastern | 0.0991% | 1,009 |
| South Asian | 0.00771% | 12,964 |
| European (non-Finnish) | 0.00407% | 24,571 |

*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}

**ATF4** population constraint: LOEUF 0.718, pLI 0.3821, missense-Z -2.1609. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **258** lies in the 'disordered' region; a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 62.95, 20% of residues very-high.

**2 experimental structure(s)** (PDB): [1CI6](https://www.rcsb.org/structure/1CI6), [9TFU](https://www.rcsb.org/structure/9TFU).

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

*Describes the biological roles of ATF4 (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:** ATF4's established molecular role includes transcription cis-regulatory region binding. p.Pro258Ala falls in the disordered region.


### Pathways affected {#pathways}

ATF4 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [NFE2L2 regulating ER-stress associated genes](https://reactome.org/content/detail/R-HSA-9818035) | curated |
| [NFE2L2 regulating anti-oxidant/detoxification enzymes](https://reactome.org/content/detail/R-HSA-9818027) | 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 |
| [PERK regulates gene expression](https://reactome.org/content/detail/R-HSA-381042) | electronic |
| [Response of EIF2AK1 (HRI) to heme deficiency](https://reactome.org/content/detail/R-HSA-9648895) | electronic |
| [Response of EIF2AK4 (GCN2) to amino acid deficiency](https://reactome.org/content/detail/R-HSA-9633012) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA binding, DNA-binding transcription factor activity, protein kinase binding, identical protein binding.

**Biological process:** positive regulation of vascular endothelial growth factor production, positive regulation of gene expression, response to nutrient levels, cellular response to oxidative stress, response to endoplasmic reticulum stress, PERK-mediated unfolded protein response.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2019-12-31.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related ATF4 variant pages (same residue, condition, or type): [ATF4 p.Pro258Leu](/variant/atf4-p-pro258leu), [ATF4 p.Ala324Val](/variant/atf4-p-ala324val), [ATF4 p.Asn131=](/variant/atf4-p-asn131), [ATF4 p.Glu322Asp](/variant/atf4-p-glu322asp), [ATF4 p.Glu3Lys](/variant/atf4-p-glu3lys), [ATF4 p.Ile208Met](/variant/atf4-p-ile208met), [ATF4 p.Thr137Ser](/variant/atf4-p-thr137ser), [ATF4 p.Tyr200=](/variant/atf4-p-tyr200).

### 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 780657). 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.*