# NM_000400.4(ERCC2):c.1867dup (p.Val623fs)

https://sugi.bio/variant/ercc2-p-val623fs

## Summary

**ERCC2 p.Val623fs (c.1867dup)** is classified **Pathogenic/Likely pathogenic** in ERCC2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-06-29). Very rare (popmax 0.00971%, nfe); Associated with ERCC2-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs756630156 · 8 submitters · 5 linked conditions · very rare (popmax 0.00971%, nfe)

## For patients & families {#patients}

This is a change in the ERCC2 gene that is considered likely disease-causing, submitted by 8 submitters, and is linked to ERCC2-related disorder.

*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 | [ERCC2](https://sugi.bio/atlas/gene/ERCC2/) |
| Protein change (HGVS p.) | p.Val623fs |
| Coding change (HGVS c.) | c.1867dup |
| MANE Select transcript | [NM_000400](https://www.ncbi.nlm.nih.gov/nuccore/NM_000400) |
| dbSNP | [rs756630156](https://www.ncbi.nlm.nih.gov/snp/rs756630156/) |
| Variant type | Duplication |
| Location | chr19:45352780-45352781 (GRCh38) |
| ClinVar | [VCV1363277](https://www.ncbi.nlm.nih.gov/clinvar/variation/1363277/) |

**All HGVS expressions:** `LRG_461:g.22807dup`, `NC_000019.10:g.45352781dup`, `NC_000019.9:g.45856039dup`, `NG_007067.2:g.22807dup`, `NM_000400.4:c.1867dup`, `NM_000400.4:c.1867dupG`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.03, GERP 1.66, phastCons 1 — highly conserved position (PP3-type support)
- 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 20 of 23**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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 **0.00971%** (nfe) · FAF95 0.00822% · FAF99 0.00764% · 114/1,174,264 in the highest group · 120/1,600,704 alleles overall — very rare (popmax 0.00971%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00971% | 10,301 |
| Remaining individuals (not grpmax-eligible) | 0.00643% | 15,555 |
| Admixed American | 0.0017% | 58,946 |
| African / African-American | 0.0014% | 71,232 |

*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 **623** lies in the 'mediates interaction with mms19' region.

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. p.Val623fs falls in the mediates interaction with mms19 region. 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 2026-06-29.

**Submitter consensus:** conflicting (7 Pathogenic, 1 Likely pathogenic).

**Submission history:** 8 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Istituto di Genetica Molecolare, National Research Council of Italy | Pathogenic | no assertion criteria provided | research |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-31 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-26 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-27 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-01 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2026-06-29 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-04-07 |

## Associated conditions {#conditions}

[ERCC2-related disorder](https://sugi.bio/atlas/disease/ercc2-related-disorder/), [xeroderma pigmentosum group D](https://sugi.bio/atlas/disease/xeroderma-pigmentosum-group-d/), [trichothiodystrophy 1, photosensitive](https://sugi.bio/atlas/disease/trichothiodystrophy-1-photosensitive/), [cerebrooculofacioskeletal syndrome 2](https://sugi.bio/atlas/disease/cerebrooculofacioskeletal-syndrome-2/), [trichothiodystrophy](https://sugi.bio/atlas/disease/trichothiodystrophy/).

**Reported phenotype names (ClinVar):** ERCC2-related disorder, not provided, Trichothiodystrophy 1, photosensitive, Cerebrooculofacioskeletal syndrome 2, Trichothiodystrophy, Xeroderma pigmentosum, group D, ERCC2-related disorders, ERCC2-related conditions, ERCC2-related condition, ERCC2-Related Xeroderma Pigmentosum.

## Similar variants {#similar}

Related ERCC2 variant pages (same residue, condition, or type): [ERCC2 p.Val623Ile](/variant/ercc2-p-val623ile), [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.His729fs](/variant/ercc2-p-his729fs), [ERCC2 p.Ile432fs](/variant/ercc2-p-ile432fs), [ERCC2 p.Leu337fs](/variant/ercc2-p-leu337fs), [ERCC2 p.Lys692fs](/variant/ercc2-p-lys692fs).

### 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 1363277). 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.*