# NM_153332.4(ERI1):c.555C>T (p.Phe185=)

https://sugi.bio/variant/eri1-p-phe185

## Summary

**ERI1 p.Phe185= (c.555C>T)** is classified **Likely benign** in ERI1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-07-01). Rare (popmax 0.321%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs139484248 · 2 submitters · rare (popmax 0.321%, afr)

## For patients & families {#patients}

This is a change in the ERI1 gene that is classified as likely 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 | [ERI1](https://sugi.bio/atlas/gene/ERI1/) |
| Protein change (HGVS p.) | p.Phe185= |
| Coding change (HGVS c.) | c.555C>T |
| MANE Select transcript | [NM_153332](https://www.ncbi.nlm.nih.gov/nuccore/NM_153332) |
| dbSNP | [rs139484248](https://www.ncbi.nlm.nih.gov/snp/rs139484248/) |
| Variant type | single nucleotide variant |
| Location | chr8:9016378-9016378 (GRCh38) |
| ClinVar | [VCV3049051](https://www.ncbi.nlm.nih.gov/clinvar/variation/3049051/) |

**All HGVS expressions:** `NC_000008.10:g.8873888C>T`, `NC_000008.11:g.9016378C>T`, `NM_001354635.2:c.321C>T`, `NM_001354636.2:c.210C>T`, `NM_001354638.2:c.555C>T`, `NM_153332.4:c.555C>T`

## 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 3.975, GERP 1.1, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.56**. 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 (C>A, Δ0.20 donor 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 **0.321%** (afr) · FAF95 0.288% · FAF99 0.275% · 240/74,718 in the highest group · 277/1,606,810 alleles overall — rare (popmax 0.321%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.321% | 311 |
| Admixed American | 0.0287% | 3,486 |
| Remaining individuals (not grpmax-eligible) | 0.0241% | 4,145 |
| European (non-Finnish) | 0.000425% | 235,180 |

*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}

**ERI1** population constraint: LOEUF 1.526, pLI 4.2781e-07, missense-Z -2.4737. *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 **185** lies in a UniProt-annotated variant site (in semdgc; likely pathogenic); a UniProt-annotated variant site (in hxal; likely pathogenic); the exonuclease domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 86.04, 77% of residues very-high.

**5 experimental structure(s)** (PDB): [1W0H](https://www.rcsb.org/structure/1W0H), [1ZBH](https://www.rcsb.org/structure/1ZBH), [1ZBU](https://www.rcsb.org/structure/1ZBU), [4L8R](https://www.rcsb.org/structure/4L8R), [4QOZ](https://www.rcsb.org/structure/4QOZ).

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

*Describes the biological roles of ERI1 (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:** ERI1's established molecular role includes 3'-5' exonuclease activity. p.Phe185= falls in the exonuclease domain.


### Pathways affected {#pathways}

ERI1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Major pathway of rRNA processing in the nucleolus and cytosol](https://reactome.org/content/detail/R-HSA-6791226) | other |

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

**Molecular function:** 3'-5' exonuclease activity.

**Biological process:** maturation of 5.8S rRNA.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-11-25 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-01 |

**Reported phenotype names (ClinVar):** ERI1-related disorder, not provided, none provided, ERI1-related condition.

## Similar variants {#similar}

Related ERI1 variant pages (same residue, condition, or type): [ERI1 p.Ser333Tyr](/variant/eri1-p-ser333tyr), [ERI1 p.Thr221Ala](/variant/eri1-p-thr221ala), [ERI1 p.Arg291=](/variant/eri1-p-arg291), [ERI1 p.Arg304Ter](/variant/eri1-p-arg304ter), [ERI1 p.Asp134Gly](/variant/eri1-p-asp134gly), [ERI1 p.Asp298Gly](/variant/eri1-p-asp298gly), [ERI1 p.Gln244Ter](/variant/eri1-p-gln244ter), [ERI1 p.Glu150Asp](/variant/eri1-p-glu150asp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 3049051). 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.*