# NM_006494.4(ERF):c.517_521dup (p.Ala175fs)

https://sugi.bio/variant/erf-p-ala175fs

## Summary

**ERF p.Ala175fs (c.517_521dup)** is classified **Likely pathogenic** in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-29). No gnomAD frequency available for this variant; Associated with Lambdoidal craniosynostosis.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2146950390 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ERF gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Lambdoidal craniosynostosis.

*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 | [ERF](https://sugi.bio/atlas/gene/ERF/) |
| Protein change (HGVS p.) | p.Ala175fs |
| Coding change (HGVS c.) | c.517_521dup |
| MANE Select transcript | [NM_006494](https://www.ncbi.nlm.nih.gov/nuccore/NM_006494) |
| dbSNP | [rs2146950390](https://www.ncbi.nlm.nih.gov/snp/rs2146950390/) |
| Variant type | Duplication |
| Location | chr19:42249590-42249591 (GRCh38) |
| ClinVar | [VCV1199415](https://www.ncbi.nlm.nih.gov/clinvar/variation/1199415/) |

**All HGVS expressions:** `NC_000019.10:g.42249594_42249598dup`, `NC_000019.9:g.42753746_42753750dup`, `NG_042802.1:g.10570_10574dup`, `NM_001301035.2:c.292_296dup`, `NM_001308402.2:c.292_296dup`, `NM_001312656.2:c.292_296dup`, `NM_006494.4:c.517_521dup`, `NM_006494.4:c.517_521dupTTCTC`

## 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 -9.689, GERP -3.37 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.443, pLI 0.99787), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (4 of 4)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ERF** population constraint: LOEUF 0.443, pLI 0.99787, missense-Z 1.658; ClinGen dosage — haploinsufficiency 3, 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):

- **craniosynostosis 4** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 55.46, 16% of residues very-high.

**2 experimental structure(s)** (PDB): [7JSA](https://www.rcsb.org/structure/7JSA), [7JSL](https://www.rcsb.org/structure/7JSL).

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

*Describes the biological roles of ERF (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:** ERF's established molecular role includes DNA-binding transcription repressor activity, RNA polymerase II-specific.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | electronic |

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

**Molecular function:** DNA-binding transcription repressor activity, RNA polymerase II-specific, sequence-specific DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-29.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Likely pathogenic | criteria provided, single submitter | research | 2021-07-29 |

## Associated conditions {#conditions}

[Lambdoidal craniosynostosis](https://sugi.bio/atlas/disease/lambdoidal-craniosynostosis/).

**Reported phenotype names (ClinVar):** Lambdoidal craniosynostosis.

## Similar variants {#similar}

Related ERF variant pages (same residue, condition, or type): [ERF p.Pro294fs](/variant/erf-p-pro294fs), [ERF p.Ala175Thr](/variant/erf-p-ala175thr), [ERF p.Asp188_Cys189insTer](/variant/erf-p-asp188-cys189inster), [ERF p.Ser24Ter](/variant/erf-p-ser24ter), [ERF p.Trp14Ter](/variant/erf-p-trp14ter), [ERF p.Arg180Cys](/variant/erf-p-arg180cys), [ERF p.Gln49Ter](/variant/erf-p-gln49ter), [ERF p.Gly53Ala](/variant/erf-p-gly53ala).

### 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 1199415). 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.*