# NM_000400.4(ERCC2):c.2251A>C (p.Lys751Gln)

https://sugi.bio/variant/ercc2-p-lys751gln

## Summary

**ERCC2 p.Lys751Gln (c.2251A>C)** is classified **Benign/Likely benign** in ERCC2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0566); Common (popmax 39.6%, mid) — too common for a highly-penetrant pathogenic allele; Associated with trichothiodystrophy 1, photosensitive.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs13181 · 12 submitters · 3 linked conditions · AlphaMissense likely benign · common (popmax 39.6%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ERCC2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 12 submitters, and is linked to trichothiodystrophy 1, photosensitive.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | ERCC2 is a diagnostic-grade gene on 9 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005270/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.Lys751Gln |
| Coding change (HGVS c.) | c.2251A>C |
| MANE Select transcript | [NM_000400](https://www.ncbi.nlm.nih.gov/nuccore/NM_000400) |
| dbSNP | [rs13181](https://www.ncbi.nlm.nih.gov/snp/rs13181/) |
| Variant type | single nucleotide variant |
| Location | chr19:45351661-45351661 (GRCh38) |
| ClinVar | [VCV134105](https://www.ncbi.nlm.nih.gov/clinvar/variation/134105/) |

**All HGVS expressions:** `LRG_461:g.23927A>C`, `LRG_461t1:c.2251A>C`, `NC_000019.10:g.45351661T>G`, `NC_000019.9:g.45854919T>G`, `NG_007067.2:g.23927A>C`, `NM_000400.4:c.2251A>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 39.6%, mid) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0566)
- REVEL 0.205 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.112 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.409, GERP -1.18, phastCons 0.997 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 12.63**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (45,351,632–45,368,730), spanning 17,098 bp. Chi-square p 0.48. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **39.6%** (mid) · FAF95 38.3% · FAF99 37.7% · 2,399/6,062 in the highest group · 567,102/1,613,486 alleles overall — common (popmax 39.6%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 42.1% | 2 |
| Finnish (not grpmax-eligible) | 41.7% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 41.3% | 2 |
| Middle Eastern (grpmax) | 39.6% | 3 |
| South Asian | 37.6% | 3 |
| European (non-Finnish) | 37.1% | 3 |
| Remaining individuals (not grpmax-eligible) | 34.2% | 3 |
| African / African-American | 22.8% | 4 |
| Admixed American | 21.8% | 5 |
| East Asian | 5.76% | 17 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **751** lies in a UniProt-annotated variant site (in).

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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (10 Benign, 3 Likely benign, 1 not provided).

**Submission history:** 14 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-03-06 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2019-02-13 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-28 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-03 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-30 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Trichothiodystrophy 1, photosensitive, not specified, Xeroderma pigmentosum, group D, Cerebrooculofacioskeletal syndrome 2, not provided, AllHighlyPenetrant, none provided, TAY SYNDROME, TRICHOTHIODYSTROPHY WITH CONGENITAL ICHTHYOSIS, PIBIDS SYNDROME.

## Cancer therapy associations (CIViC) {#civic}

Curated clinical evidence for this variant from CIViC (profile *K751Q*):

| Disease | Therapies | Type | Level | Significance |
| --- | --- | --- | --- | --- |
| Osteosarcoma | Cisplatin | Predictive | B | Resistance |
| Lung Non-small Cell Carcinoma | Paclitaxel,Carboplatin | Predictive | B | Sensitivity/Response |
*CIViC evidence levels A–E (A strongest). Therapy associations are context-specific — not a treatment recommendation.*

## Pharmacogenomics (PharmGKB) {#pgx}

Clinical drug-response annotations:

| Drug(s) | Evidence level | Category | Phenotype |
| --- | --- | --- | --- |
| fluorouracil;leucovorin;oxaliplatin | 3 | Efficacy,Toxicity | Colorectal Neoplasms |
| Platinum compounds | 3 | Toxicity | Non-Small Cell Lung Carcinoma |
| bleomycin;cisplatin;etoposide | 3 | Toxicity | Alopecia;Testicular Neoplasms |
| cisplatin;doxorubicin;methotrexate | 3 | Toxicity | Nephrotoxicity;Osteosarcoma |
| cisplatin;gemcitabine | 3 | Efficacy | Mesothelioma |
*PharmGKB levels 1A/1B (highest) → 4. Discuss any medication decision with your prescriber — reference information, not advice.*

## Similar variants {#similar}

Related ERCC2 variant pages (same residue, condition, or type): [ERCC2 p.Lys751Arg](/variant/ercc2-p-lys751arg), [ERCC2 p.Lys751=](/variant/ercc2-p-lys751), [ERCC2 p.Lys751Ter](/variant/ercc2-p-lys751ter), [ERCC2 c.1238-1G>C](/variant/ercc2-c-1238-minus-1g-c), [ERCC2 c.1308-2A>G](/variant/ercc2-c-1308-minus-2a-g), [ERCC2 c.1378-1G>T](/variant/ercc2-c-1378-minus-1g-t), [ERCC2 c.1479+2T>C](/variant/ercc2-c-1479-plus-2t-c), [ERCC2 c.1480-1G>C](/variant/ercc2-c-1480-minus-1g-c).

### 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 134105). 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.*