# NM_005236.3(ERCC4):c.217A>G (p.Ile73Val)

https://sugi.bio/variant/ercc4-p-ile73val

## Summary

**ERCC4 p.Ile73Val (c.217A>G)** is classified **Uncertain significance** in ERCC4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-07-25). AlphaMissense: likely benign (0.105); Ultra-rare (popmax 0.0384%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs141591400 · 7 submitters · 5 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0384%, 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 7 submitters, and is linked to Inborn genetic diseases.

*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.*

**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.Ile73Val |
| Coding change (HGVS c.) | c.217A>G |
| MANE Select transcript | [NM_005236](https://www.ncbi.nlm.nih.gov/nuccore/NM_005236) |
| dbSNP | [rs141591400](https://www.ncbi.nlm.nih.gov/snp/rs141591400/) |
| Variant type | single nucleotide variant |
| Location | chr16:13922040-13922040 (GRCh38) |
| ClinVar | [VCV134143](https://www.ncbi.nlm.nih.gov/clinvar/variation/134143/) |

**All HGVS expressions:** `LRG_463:g.6884A>G`, `LRG_463t1:c.217A>G`, `NC_000016.10:g.13922040A>G`, `NC_000016.9:g.14015897A>G`, `NG_011442.1:g.6884A>G`, `NM_005236.3:c.217A>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.105)
- REVEL 0.118 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.28 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 9.295, GERP 1.41, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.7**. 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: **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 **0.0384%** (nfe) · FAF95 0.0355% · FAF99 0.0343% · 453/1,179,196 in the highest group · 513/1,613,224 alleles overall — ultra-rare (popmax 0.0384%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0464% | 2,154 |
| European (non-Finnish) (grpmax) | 0.0384% | 2,603 |
| Admixed American | 0.0317% | 3,159 |
| Middle Eastern | 0.0165% | 6,062 |
| African / African-American | 0.012% | 8,338 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,012 |
| South Asian | 0.0011% | 91,056 |

Remaining individuals 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 **73** lies in the 'helicase-like' 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.Ile73Val falls in the helicase-like region.


### 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 2024-07-25.

**Submitter consensus:** conflicting (7 Uncertain significance, 1 not provided).

**Submission history:** 8 submissions (2013–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-09 |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-25 |
| St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-04 |
| St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-25 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [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):** Inborn genetic diseases, not specified, Cockayne syndrome, Fanconi anemia complementation group Q, Xeroderma pigmentosum, group F, not provided, XFE progeroid syndrome, ERCC4-Related Xeroderma Pigmentosum, XERODERMA PIGMENTOSUM, TYPE F, Xeroderma pigmentosum, type 6.

## Similar variants {#similar}

Related ERCC4 variant pages (same residue, condition, or type): [ERCC4 p.Ile73=](/variant/ercc4-p-ile73), [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), [ERCC4 p.Cys236Arg](/variant/ercc4-p-cys236arg).

### 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 134143). 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.*