# NM_000400.4(ERCC2):c.1962C>T (p.Phe654=)

https://sugi.bio/variant/ercc2-p-phe654

## Summary

**ERCC2 p.Phe654= (c.1962C>T)** is classified **Conflicting classifications of pathogenicity** in ERCC2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-22). Ultra-rare (popmax 0.0267%, eas); Associated with xeroderma pigmentosum group D.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs762985501 · 6 submitters · 2 linked conditions · ultra-rare (popmax 0.0267%, eas)

## For patients & families {#patients}

This is a change in the ERCC2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to xeroderma pigmentosum group D.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | ERCC2 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of Xeroderma pigmentosum-Cockayne syndrome complex** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hydrocephalus — Very frequent (99-80%)
- Microcephaly — Very frequent (99-80%)
- Hearing impairment — Very frequent (99-80%)
- Retinopathy — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)
- Optic atrophy — Very frequent (99-80%)
- Dry skin — Very frequent (99-80%)
- Skin rash — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016452/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.Phe654= |
| Coding change (HGVS c.) | c.1962C>T |
| MANE Select transcript | [NM_000400](https://www.ncbi.nlm.nih.gov/nuccore/NM_000400) |
| dbSNP | [rs762985501](https://www.ncbi.nlm.nih.gov/snp/rs762985501/) |
| Variant type | single nucleotide variant |
| Location | chr19:45352590-45352590 (GRCh38) |
| ClinVar | [VCV329506](https://www.ncbi.nlm.nih.gov/clinvar/variation/329506/) |

**All HGVS expressions:** `LRG_461:g.22998C>T`, `LRG_461t1:c.1962C>T`, `NC_000019.10:g.45352590G>A`, `NC_000019.9:g.45855848G>A`, `NG_007067.2:g.22998C>T`, `NM_000400.4:c.1962C>T`

## 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 -3.921, GERP -3.04 — fast-evolving / accelerated position
- CADD: **PHRED 0.478**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.65 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0267%** (eas) · FAF95 0.0154% · FAF99 0.0121% · 12/44,884 in the highest group · 214/1,613,932 alleles overall — ultra-rare (popmax 0.0267%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.27% | 370 |
| East Asian (grpmax) | 0.0267% | 3,740 |
| Remaining individuals (not grpmax-eligible) | 0.0256% | 3,906 |
| Admixed American | 0.0133% | 7,501 |
| European (non-Finnish) | 0.00797% | 12,554 |
| African / African-American | 0.00534% | 18,732 |

Ashkenazi Jewish 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 **654** lies in an α-helix.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-22.

**Submitter consensus:** conflicting (4 Likely benign, 1 Uncertain significance, 1 Benign).

**Submission history:** 6 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-22 |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2021-01-31 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-07 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-01 |

## Associated conditions {#conditions}

[xeroderma pigmentosum group D](https://sugi.bio/atlas/disease/xeroderma-pigmentosum-group-d/), [xeroderma pigmentosum](https://sugi.bio/atlas/disease/xeroderma-pigmentosum/).

**Reported phenotype names (ClinVar):** Xeroderma pigmentosum, group D, not provided, Xeroderma pigmentosum, Inborn genetic diseases, not specified, XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D, XERODERMA PIGMENTOSUM IV, XP, GROUP D, XP, GROUP H, ERCC2-Related Xeroderma Pigmentosum.

## Same-residue context {#hotspot}

Residue **654** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ERCC2 p.Phe654fs](/variant/ercc2-p-phe654fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ERCC2 variant pages (same residue, condition, or type): [ERCC2 c.1308-2A>G](/variant/ercc2-c-1308-minus-2a-g), [ERCC2 c.1480-2A>C](/variant/ercc2-c-1480-minus-2a-c), [ERCC2 c.1666-2A>T](/variant/ercc2-c-1666-minus-2a-t), [ERCC2 c.1759-2A>G](/variant/ercc2-c-1759-minus-2a-g), [ERCC2 c.183+2T>A](/variant/ercc2-c-183-plus-2t-a), [ERCC2 c.361-1G>A](/variant/ercc2-c-361-minus-1g-a), [ERCC2 c.816-2A>G](/variant/ercc2-c-816-minus-2a-g), [ERCC2 p.Ala717Gly](/variant/ercc2-p-ala717gly).

### 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 329506). 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.*