# NM_005236.3(ERCC4):c.2074C>T (p.Arg692Ter)

https://sugi.bio/variant/ercc4-p-arg692ter

## Summary

**ERCC4 p.Arg692Ter (c.2074C>T)** is classified **Pathogenic** in ERCC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-13). Very rare (popmax 0.000169%, nfe); Associated with xeroderma pigmentosum group F.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 3 linked conditions · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the ERCC4 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to xeroderma pigmentosum group F.

*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 | ERCC4 is a diagnostic-grade gene on 18 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/0005628/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ERCC4](https://sugi.bio/atlas/gene/ERCC4/) |
| Protein change (HGVS p.) | p.Arg692Ter |
| Coding change (HGVS c.) | c.2074C>T |
| MANE Select transcript | [NM_005236](https://www.ncbi.nlm.nih.gov/nuccore/NM_005236) |
| Variant type | single nucleotide variant |
| Location | chr16:13947670-13947670 (GRCh38) |
| ClinVar | [VCV4783221](https://www.ncbi.nlm.nih.gov/clinvar/variation/4783221/) |

**All HGVS expressions:** `LRG_463:g.32514C>T`, `LRG_463t1:c.2074C>T`, `NC_000016.10:g.13947670C>T`, `NC_000016.9:g.14041527C>T`, `NG_011442.1:g.32514C>T`, `NM_005236.3:c.2074C>T`

## 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 4.004, GERP 0.774, phastCons 0.999 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.984, pLI 3.5282e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (11 of 11)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 42.0**. 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** — 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 **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,180,034 in the highest group · 3/1,614,056 alleles overall — very rare (popmax 0.000169%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 64,032 |
| European (non-Finnish) (grpmax) | 0.000169% | 590,016 |

Finnish 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}

**ERCC4** population constraint: LOEUF 0.984, pLI 3.5282e-11, missense-Z -0.57103; ClinGen dosage — haploinsufficiency 30, 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):

- **xeroderma pigmentosum group F** — Definitive (AR)

## Protein context {#protein}

Residue **692** lies in the ercc4 domain; the 'nuclease' region.

AlphaFold model confidence (whole protein): pLDDT 74.60, 17% of residues very-high.

**13 experimental structure(s)** (PDB): [1Z00](https://www.rcsb.org/structure/1Z00), [2A1J](https://www.rcsb.org/structure/2A1J), [2AQ0](https://www.rcsb.org/structure/2AQ0), [2KN7](https://www.rcsb.org/structure/2KN7), [2MUT](https://www.rcsb.org/structure/2MUT), [6SXA](https://www.rcsb.org/structure/6SXA) — incl. mutant structure 2MUT.

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

*Describes the biological roles of ERCC4 (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:** ERCC4's established molecular role includes single-stranded DNA endonuclease activity. p.Arg692Ter falls in the ercc4 domain.


### Pathways affected {#pathways}

ERCC4 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [Fanconi Anemia Pathway](https://reactome.org/content/detail/R-HSA-6783310) | curated |
| [Formation of Incision Complex in GG-NER](https://reactome.org/content/detail/R-HSA-5696395) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |

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

**Molecular function:** single-stranded DNA endonuclease activity, damaged DNA binding, single-stranded DNA binding, DNA endonuclease activity, protein-macromolecule adaptor activity, identical protein binding.

**Biological process:** telomere maintenance, double-strand break repair via homologous recombination, DNA repair, nucleotide-excision repair, double-strand break repair via nonhomologous end joining, response to UV.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-13.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-13 |

## Associated conditions {#conditions}

[xeroderma pigmentosum group F](https://sugi.bio/atlas/disease/xeroderma-pigmentosum-group-f/), [Fanconi anemia complementation group Q](https://sugi.bio/atlas/disease/fanconi-anemia-complementation-group-q/), [Cockayne syndrome](https://sugi.bio/atlas/disease/cockayne-syndrome/).

**Reported phenotype names (ClinVar):** Xeroderma pigmentosum, group F, Cockayne syndrome, Fanconi anemia complementation group Q, ERCC4-Related Xeroderma Pigmentosum, XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP F, XERODERMA PIGMENTOSUM, TYPE F, Xeroderma pigmentosum, type 6, XERODERMA PIGMENTOSUM VI, XP, GROUP F.

## Similar variants {#similar}

Related ERCC4 variant pages (same residue, condition, or type): [ERCC4 p.Arg692Gln](/variant/ercc4-p-arg692gln), [ERCC4 p.Arg692Pro](/variant/ercc4-p-arg692pro), [ERCC4 c.1102+1G>T](/variant/ercc4-c-1102-plus-1g-t), [ERCC4 c.793-2A>G](/variant/ercc4-c-793-minus-2a-g), [ERCC4 p.Arg20Ter](/variant/ercc4-p-arg20ter), [ERCC4 p.Arg589Trp](/variant/ercc4-p-arg589trp), [ERCC4 p.Arg689Ser](/variant/ercc4-p-arg689ser), [ERCC4 p.Arg772Ter](/variant/ercc4-p-arg772ter).

### 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 4783221). 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.*