# NM_005236.3(ERCC4):c.1787C>A (p.Ala596Glu)

https://sugi.bio/variant/ercc4-p-ala596glu

## Summary

**ERCC4 p.Ala596Glu (c.1787C>A)** is classified **Conflicting classifications of pathogenicity** in ERCC4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-24). AlphaMissense: likely pathogenic (0.9839); Ultra-rare (popmax 0.0245%, eas); Associated with ovarian cancer.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs751782722 · 2 submitters · 4 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0245%, eas)

## For patients & families {#patients}

This is a change in the ERCC4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to ovarian cancer.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 2647 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [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.Ala596Glu |
| Coding change (HGVS c.) | c.1787C>A |
| MANE Select transcript | [NM_005236](https://www.ncbi.nlm.nih.gov/nuccore/NM_005236) |
| dbSNP | [rs751782722](https://www.ncbi.nlm.nih.gov/snp/rs751782722/) |
| Variant type | single nucleotide variant |
| Location | chr16:13935719-13935719 (GRCh38) |
| ClinVar | [VCV662825](https://www.ncbi.nlm.nih.gov/clinvar/variation/662825/) |

**All HGVS expressions:** `LRG_463:g.20563C>A`, `LRG_463t1:c.1787C>A`, `NC_000016.10:g.13935719C>A`, `NC_000016.9:g.14029576C>A`, `NG_011442.1:g.20563C>A`, `NM_005236.3:c.1787C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9839)
- REVEL 0.517 (indeterminate)
- SaProt LLR -10.965 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.681, GERP 1.53, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in ERCC4 (of 5,379 modeled).
- CADD: **PHRED 26.6**. 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 1.08** across the covering region of the MANE Select transcript (13,920,166–13,948,344), spanning 28,178 bp. Chi-square p 0.011. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.97 donor 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 **0.0245%** (eas) · FAF95 0.0137% · FAF99 0.0106% · 11/44,896 in the highest group · 11/1,613,626 alleles overall — ultra-rare (popmax 0.0245%, eas).

*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}


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.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-02-24.

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

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-24 |
| Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-01-01 |

## Associated conditions {#conditions}

[ovarian cancer](https://sugi.bio/atlas/disease/ovarian-cancer/), [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):** Ovarian cancer, Cockayne syndrome, Fanconi anemia complementation group Q, Xeroderma pigmentosum, group F, OVARIAN CANCER, SOMATIC, XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP F, XERODERMA PIGMENTOSUM VI, XP, GROUP F, XERODERMA PIGMENTOSUM, TYPE F, Xeroderma pigmentosum, type 6.

## Similar variants {#similar}

Related ERCC4 variant pages (same residue, condition, or type): [ERCC4 p.Ala596Val](/variant/ercc4-p-ala596val), [ERCC4 p.Ala596=](/variant/ercc4-p-ala596), [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 662825). 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.*