# NM_000400.4(ERCC2):c.1293dup (p.Ile432fs)

https://sugi.bio/variant/ercc2-p-ile432fs

## Summary

**ERCC2 p.Ile432fs (c.1293dup)** is classified **Pathogenic/Likely pathogenic** in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-19). Very rare (popmax 0.000339%, nfe); Associated with cerebrooculofacioskeletal syndrome 2.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1266915084 · 2 submitters · 1 linked condition · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the ERCC2 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to cerebrooculofacioskeletal syndrome 2.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015497/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ERCC2](https://sugi.bio/atlas/gene/ERCC2/) |
| Protein change (HGVS p.) | p.Ile432fs |
| Coding change (HGVS c.) | c.1293dup |
| MANE Select transcript | [NM_000400](https://www.ncbi.nlm.nih.gov/nuccore/NM_000400) |
| dbSNP | [rs1266915084](https://www.ncbi.nlm.nih.gov/snp/rs1266915084/) |
| Variant type | Duplication |
| Location | chr19:45357643-45357644 (GRCh38) |
| ClinVar | [VCV2675043](https://www.ncbi.nlm.nih.gov/clinvar/variation/2675043/) |

**All HGVS expressions:** `LRG_461:g.17944dup`, `LRG_461t1:c.1290dup`, `NC_000019.10:g.45357647dup`, `NC_000019.9:g.45860905dup`, `NG_007067.2:g.17944dup`, `NM_000400.4:c.1293dup`

## 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 -1.983, GERP -1.84 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.089, pLI 6.8729e-28. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 23**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 26.1**. 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: **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 (gnomAD v4.1): grpmax **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,179,990 in the highest group · 4/1,613,892 alleles overall — very rare (popmax 0.000339%, 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}

**ERCC2** population constraint: LOEUF 1.089, pLI 6.8729e-28, missense-Z 0.6086; ClinGen dosage — haploinsufficiency 30, triplosensitivity 40 (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):

- **complex hereditary spastic paraplegia** — Definitive (AR)
- **xeroderma pigmentosum group D** — Definitive (AR)

## Protein context {#protein}

Residue **432** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 87.74, 53% of residues very-high.

**55 experimental structure(s)** (PDB): [28JM](https://www.rcsb.org/structure/28JM), [28JS](https://www.rcsb.org/structure/28JS), [28JV](https://www.rcsb.org/structure/28JV), [28KE](https://www.rcsb.org/structure/28KE), [29VF](https://www.rcsb.org/structure/29VF), [29WD](https://www.rcsb.org/structure/29WD).

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

*Describes the biological roles of ERCC2 (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:** ERCC2's established molecular role includes protein-macromolecule adaptor activity. In Reactome, ERCC2 is annotated in disease pathway(s) including **Formation of HIV elongation complex in the absence of HIV Tat**, **Formation of HIV-1 elongation complex containing HIV-1 Tat**.

**Disease mechanism (Reactome):** ERCC2 loss or alteration is curated in [Formation of HIV elongation complex in the absence of HIV Tat](https://reactome.org/content/detail/R-HSA-167152), [Formation of HIV-1 elongation complex containing HIV-1 Tat](https://reactome.org/content/detail/R-HSA-167200), [Formation of the HIV-1 Early Elongation Complex](https://reactome.org/content/detail/R-HSA-167158).

### Pathways affected {#pathways}

ERCC2 participates in **30 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Formation of HIV elongation complex in the absence of HIV Tat](https://reactome.org/content/detail/R-HSA-167152) | electronic |
| ⚕ [Formation of HIV-1 elongation complex containing HIV-1 Tat](https://reactome.org/content/detail/R-HSA-167200) | electronic |
| ⚕ [Formation of the HIV-1 Early Elongation Complex](https://reactome.org/content/detail/R-HSA-167158) | electronic |
| ⚕ [HIV Transcription Initiation](https://reactome.org/content/detail/R-HSA-167161) | electronic |
| ⚕ [RNA Pol II CTD phosphorylation and interaction with CE during HIV infection](https://reactome.org/content/detail/R-HSA-167160) | electronic |
| ⚕ [RNA Polymerase II HIV Promoter Escape](https://reactome.org/content/detail/R-HSA-167162) | electronic |
| ⚕ [Tat-mediated elongation of the HIV-1 transcript](https://reactome.org/content/detail/R-HSA-167246) | electronic |
| ⚕ [Transcription of the HIV genome](https://reactome.org/content/detail/R-HSA-167172) | electronic |
| [Dual Incision in GG-NER](https://reactome.org/content/detail/R-HSA-5696400) | curated |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Formation of Incision Complex in GG-NER](https://reactome.org/content/detail/R-HSA-5696395) | curated |
| [Formation of RNA Pol II elongation complex ](https://reactome.org/content/detail/R-HSA-112382) | curated |
| [Formation of TC-NER Pre-Incision Complex](https://reactome.org/content/detail/R-HSA-6781823) | curated |
| [Formation of the Early Elongation Complex](https://reactome.org/content/detail/R-HSA-113418) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [RNA Pol II CTD phosphorylation and interaction with CE](https://reactome.org/content/detail/R-HSA-77075) | curated |
| [RNA Polymerase I Promoter Escape](https://reactome.org/content/detail/R-HSA-73772) | curated |
| [RNA Polymerase I Transcription Initiation](https://reactome.org/content/detail/R-HSA-73762) | curated |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Promoter Escape](https://reactome.org/content/detail/R-HSA-73776) | curated |
| [RNA Polymerase II Transcription Elongation](https://reactome.org/content/detail/R-HSA-75955) | curated |
| [RNA Polymerase II Transcription Initiation](https://reactome.org/content/detail/R-HSA-75953) | curated |
| [RNA Polymerase II Transcription Initiation And Promoter Clearance](https://reactome.org/content/detail/R-HSA-76042) | curated |
| [RNA Polymerase II Transcription Pre-Initiation And Promoter Opening](https://reactome.org/content/detail/R-HSA-73779) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |
| [mRNA Capping](https://reactome.org/content/detail/R-HSA-72086) | curated |
| [Cytosolic iron-sulfur cluster assembly](https://reactome.org/content/detail/R-HSA-2564830) | electronic |
| [NoRC negatively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-427413) | electronic |
| [RNA Polymerase I Transcription Termination](https://reactome.org/content/detail/R-HSA-73863) | electronic |

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

**Molecular function:** protein-macromolecule adaptor activity, 5'-3' DNA helicase activity.

**Biological process:** transcription-coupled nucleotide-excision repair, nucleotide-excision repair, regulation of transcription by RNA polymerase II, transcription by RNA polymerase II, transcription initiation at RNA polymerase II promoter, apoptotic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-09-19.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-07-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-19 |

## Associated conditions {#conditions}

[cerebrooculofacioskeletal syndrome 2](https://sugi.bio/atlas/disease/cerebrooculofacioskeletal-syndrome-2/).

**Reported phenotype names (ClinVar):** Cerebrooculofacioskeletal syndrome 2, not provided, none provided.

## Similar variants {#similar}

Related ERCC2 variant pages (same residue, condition, or type): [ERCC2 c.1377+1dup](/variant/ercc2-c-1377-plus-1dup), [ERCC2 c.1479+2dup](/variant/ercc2-c-1479-plus-2dup), [ERCC2 p.Ala600fs](/variant/ercc2-p-ala600fs), [ERCC2 p.Leu337fs](/variant/ercc2-p-leu337fs), [ERCC2 p.Lys692fs](/variant/ercc2-p-lys692fs), [ERCC2 p.Phe720fs](/variant/ercc2-p-phe720fs), [ERCC2 p.Tyr625fs](/variant/ercc2-p-tyr625fs), [ERCC2 p.Val623fs](/variant/ercc2-p-val623fs).

### 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 2675043). 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.*