# NM_005236.3(ERCC4):c.1728A>T (p.Arg576Ser)

https://sugi.bio/variant/ercc4-p-arg576ser

## Summary

**ERCC4 p.Arg576Ser (c.1728A>T)** is classified **Uncertain significance** in ERCC4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-05-15). AlphaMissense: ambiguous (0.549); Very rare (popmax 0.00924%, nfe); Associated with xeroderma pigmentosum group F.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs765454246 · 5 submitters · 4 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00924%, nfe)

## For patients & families {#patients}

This is a change in the ERCC4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 5 submitters, 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.Arg576Ser |
| Coding change (HGVS c.) | c.1728A>T |
| MANE Select transcript | [NM_005236](https://www.ncbi.nlm.nih.gov/nuccore/NM_005236) |
| dbSNP | [rs765454246](https://www.ncbi.nlm.nih.gov/snp/rs765454246/) |
| Variant type | single nucleotide variant |
| Location | chr16:13935660-13935660 (GRCh38) |
| ClinVar | [VCV317816](https://www.ncbi.nlm.nih.gov/clinvar/variation/317816/) |

**All HGVS expressions:** `LRG_463:g.20504A>T`, `LRG_463t1:c.1728A>T`, `NC_000016.10:g.13935660A>T`, `NC_000016.9:g.14029517A>T`, `NG_011442.1:g.20504A>T`, `NM_005236.3:c.1728A>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.549) — no call either way
- REVEL 0.093 (moderately benign-leaning)
- SaProt LLR -4.95 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 3.506, GERP -2.61, phastCons 1 — highly conserved
- CADD: **PHRED 18.58**. 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 (A>G, Δ1.00 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 **0.00924%** (nfe) · FAF95 0.00782% · FAF99 0.00727% · 109/1,180,014 in the highest group · 122/1,614,018 alleles overall — very rare (popmax 0.00924%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0141% | 7,116 |
| European (non-Finnish) (grpmax) | 0.00924% | 10,826 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,243 |
| Admixed American | 0.00167% | 59,990 |
| African / African-American | 0.00133% | 74,912 |

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

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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-05-15.

**Submitter consensus:** unanimous (6/6 Uncertain significance).

**Submission history:** 6 submissions (2018–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-06-05 |
| St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-31 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-01 |
| St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-15 |

## Associated conditions {#conditions}

[xeroderma pigmentosum group F](https://sugi.bio/atlas/disease/xeroderma-pigmentosum-group-f/), [XFE progeroid syndrome](https://sugi.bio/atlas/disease/xfe-progeroid-syndrome/), [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, Fanconi anemia complementation group Q, Cockayne syndrome, XFE progeroid syndrome, XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP F, XERODERMA PIGMENTOSUM VI, XP, GROUP F, ERCC4-Related Xeroderma Pigmentosum, XERODERMA PIGMENTOSUM, TYPE F, Xeroderma pigmentosum, type 6.

## Same-residue context {#hotspot}

Residue **576** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ERCC4 p.Arg576_Tyr577insTer](/variant/ercc4-p-arg576-tyr577inster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ERCC4 variant pages (same residue, condition, or type): [ERCC4 p.Arg576Thr](/variant/ercc4-p-arg576thr), [ERCC4 p.Arg576=](/variant/ercc4-p-arg576), [ERCC4 p.Arg576_Tyr577insTer](/variant/ercc4-p-arg576-tyr577inster), [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).

### 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 317816). 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.*