# NM_006494.4(ERF):c.1201_1202del (p.Lys401fs)

https://sugi.bio/variant/erf-p-lys401fs

## Summary

**ERF p.Lys401fs (c.1201_1202del)** is classified **Pathogenic/Likely pathogenic** in ERF (ClinVar, Multiple submitters, 19 submitters; last evaluated 2025-07-07). Very rare (popmax 0.000254%, nfe); Associated with Noonan-like syndrome.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1064794325 · 19 submitters · 6 linked conditions · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the ERF gene that is considered likely disease-causing, submitted by 19 submitters, and is linked to Noonan-like syndrome.

*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.Lys401fs |
| Coding change (HGVS c.) | c.1201_1202del |
| MANE Select transcript | [NM_006494](https://www.ncbi.nlm.nih.gov/nuccore/NM_006494) |
| dbSNP | [rs1064794325](https://www.ncbi.nlm.nih.gov/snp/rs1064794325/) |
| Variant type | Deletion |
| Location | chr19:42248910-42248911 (GRCh38) |
| ClinVar | [VCV420168](https://www.ncbi.nlm.nih.gov/clinvar/variation/420168/) |

**All HGVS expressions:** `NC_000019.10:g.42248910_42248911del`, `NC_000019.9:g.42753062_42753063del`, `NG_042802.1:g.11254_11255del`, `NM_001301035.2:c.976_977del`, `NM_001308402.2:c.976_977del`, `NM_001312656.2:c.976_977del`, `NM_006494.2:c.1201_1202del`, `NM_006494.3:c.1201_1202delAA`, `NM_006494.4:c.1201_1202del`, `NM_006494.4:c.1201_1202delAA`

## 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 0.304, GERP -1.05, phastCons 0.024 — weakly conserved 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 deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,598 in the highest group · 3/1,455,378 alleles overall — very rare (popmax 0.000254%, nfe).

*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}

Residue **401** lies in the 'disordered' region.

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. p.Lys401fs falls in the disordered region.


### 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-07.

**Submitter consensus:** conflicting (16 Pathogenic, 3 Likely pathogenic).

**Submission history:** 19 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Medical Genetics, Oslo University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2017-06-21 |
| Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-12-22 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-10 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-23 |
| Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital | Pathogenic | criteria provided, single submitter | research | 2023-12-31 |
| Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-12 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-08-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-07 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-04-11 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-21 |
| Department of Medical Genetics, Tohoku University School of Medicine | Pathogenic | criteria provided, single submitter | research | 2025-01-10 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-23 |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-23 |
| Department of Endocrinology and Genetics, Fuzhou Children’s Hospital of Fujian Medical University | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-11 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-30 |
| Department of Human Genetics, Hannover Medical School | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-17 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2021-12-01 |

## Associated conditions {#conditions}

[Noonan-like syndrome](https://sugi.bio/atlas/disease/noonan-like-syndrome/), [TWIST1-related craniosynostosis](https://sugi.bio/atlas/disease/twist1-related-craniosynostosis/), [craniosynostosis 4](https://sugi.bio/atlas/disease/craniosynostosis-4/), [Chitayat syndrome](https://sugi.bio/atlas/disease/chitayat-syndrome/), [Noonan syndrome](https://sugi.bio/atlas/disease/noonan-syndrome/), [neurodevelopmental disorder](https://sugi.bio/atlas/disease/neurodevelopmental-disorder/).

**Reported phenotype names (ClinVar):** Noonan-like syndrome, not provided, Lambdoidal craniosynostosis, Neurodevelopmental disorder, TWIST1-related craniosynostosis, Chitayat syndrome, ERF-related disorder, Noonan Syndrome-like developmental disorder, Noonan syndrome, Craniosynostosis 4.

## Similar variants {#similar}

Related ERF variant pages (same residue, condition, or type): [ERF p.Lys401Glu](/variant/erf-p-lys401glu), [ERF p.Arg143fs](/variant/erf-p-arg143fs), [ERF p.Asp188_Cys189insTer](/variant/erf-p-asp188-cys189inster), [ERF p.Gly299fs](/variant/erf-p-gly299fs), [ERF p.Pro358fs](/variant/erf-p-pro358fs), [ERF p.Ser304del](/variant/erf-p-ser304del), [ERF c.-44_22+11del](/variant/erf-c-minus-44-22-plus-11del), [ERF p.Gln341fs](/variant/erf-p-gln341fs).

### 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 420168). 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.*