# NM_033266.4(ERN2):c.1416T>C (p.Phe472=)

https://sugi.bio/variant/ern2-p-phe472

## Summary

**ERN2 p.Phe472= (c.1416T>C)** is classified **Benign** in ERN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-02-26). Rare (popmax 0.614%, afr).

**At a glance:** Benign · review: Single submitter · rsID rs74012349 · 1 submitter · rare (popmax 0.614%, afr)

## For patients & families {#patients}

This is a change in the ERN2 gene that is classified as benign — not considered disease-causing, 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 | [ERN2](https://sugi.bio/atlas/gene/ERN2/) |
| Protein change (HGVS p.) | p.Phe472= |
| Coding change (HGVS c.) | c.1416T>C |
| MANE Select transcript | [NM_033266](https://www.ncbi.nlm.nih.gov/nuccore/NM_033266) |
| dbSNP | [rs74012349](https://www.ncbi.nlm.nih.gov/snp/rs74012349/) |
| Variant type | single nucleotide variant |
| Location | chr16:23700648-23700648 (GRCh38) |
| ClinVar | [VCV736800](https://www.ncbi.nlm.nih.gov/clinvar/variation/736800/) |

**All HGVS expressions:** `NC_000016.10:g.23700648A>G`, `NC_000016.9:g.23711969A>G`, `NM_001308220.2:c.1260T>C`, `NM_033266.4:c.1416T>C`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 0.722, GERP -0.59, phastCons 0.021 — weakly conserved position
- CADD: **PHRED 1.66**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.23 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.614%** (afr) · FAF95 0.568% · FAF99 0.55% · 461/75,050 in the highest group · 530/1,614,124 alleles overall — rare (popmax 0.614%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.614% | 163 |
| Remaining individuals (not grpmax-eligible) | 0.0656% | 1,525 |
| Admixed American | 0.04% | 2,501 |
| South Asian | 0.0011% | 91,082 |
| European (non-Finnish) | 0.000254% | 393,335 |

*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}

**ERN2** population constraint: LOEUF 1.209, pLI 9.9981e-37, missense-Z 0.0027208. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 70.91, 33% of residues very-high.

**2 experimental structure(s)** (PDB): [9I3F](https://www.rcsb.org/structure/9I3F), [9I3U](https://www.rcsb.org/structure/9I3U).

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

*Describes the biological roles of ERN2 (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:** ERN2's established molecular role includes magnesium ion binding.


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

**Molecular function:** magnesium ion binding, endonuclease activity, protein serine/threonine kinase activity, ATP binding.

**Biological process:** protein phosphorylation, rRNA catabolic process, apoptotic chromosome condensation, negative regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-02-26.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-02-26 |

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

## Similar variants {#similar}

Related ERN2 variant pages (same residue, condition, or type): [ERN2 p.Arg868Ter](/variant/ern2-p-arg868ter), [ERN2 p.Val69Ile](/variant/ern2-p-val69ile), [ERN2 p.Ala22Val](/variant/ern2-p-ala22val), [ERN2 p.Ala318Asp](/variant/ern2-p-ala318asp), [ERN2 p.Ala395Val](/variant/ern2-p-ala395val), [ERN2 p.Ala4Thr](/variant/ern2-p-ala4thr), [ERN2 p.Ala760Thr](/variant/ern2-p-ala760thr), [ERN2 p.Ala80Thr](/variant/ern2-p-ala80thr).

### 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 736800). 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.*