# NM_032444.4(SLX4):c.5177C>T (p.Ala1726Val)

https://sugi.bio/variant/slx4-p-ala1726val

## Summary

**SLX4 p.Ala1726Val (c.5177C>T)** is classified **Conflicting classifications of pathogenicity** in SLX4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-01-25). AlphaMissense: likely benign (0.119); Rare (popmax 0.107%, eas); Associated with Fanconi anemia.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs752633436 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.107%, eas)

## For patients & families {#patients}

This is a change in the SLX4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 submitters, and is linked to Fanconi anemia.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Clinical trials | 85 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SLX4 is a diagnostic-grade gene on 19 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006425/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SLX4](https://sugi.bio/atlas/gene/SLX4/) |
| Protein change (HGVS p.) | p.Ala1726Val |
| Coding change (HGVS c.) | c.5177C>T |
| MANE Select transcript | [NM_032444](https://www.ncbi.nlm.nih.gov/nuccore/NM_032444) |
| dbSNP | [rs752633436](https://www.ncbi.nlm.nih.gov/snp/rs752633436/) |
| Variant type | single nucleotide variant |
| Location | chr16:3582670-3582670 (GRCh38) |
| ClinVar | [VCV843315](https://www.ncbi.nlm.nih.gov/clinvar/variation/843315/) |

**All HGVS expressions:** `LRG_503:g.33915C>T`, `LRG_503t1:c.5177C>T`, `NC_000016.10:g.3582670G>A`, `NC_000016.9:g.3632671G>A`, `NG_028123.1:g.33915C>T`, `NM_032444.4:c.5177C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.119)
- REVEL 0.077 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.799 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.433, GERP -2.74 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 11.07**. 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 1.07** across the covering region of the MANE Select transcript (3,582,345–3,608,964), spanning 26,619 bp. Chi-square p 0.0005. 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 (G>C, Δ0.26 acceptor loss), 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 **0.107%** (eas) · FAF95 0.0829% · FAF99 0.0743% · 48/44,884 in the highest group · 62/1,612,682 alleles overall — rare (popmax 0.107%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.107% | 935 |
| Middle Eastern | 0.0165% | 6,062 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,832 |
| Admixed American | 0.00333% | 30,005 |
| South Asian | 0.0022% | 45,540 |
| European (non-Finnish) | 0.000508% | 196,664 |

*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}

**SLX4** population constraint: LOEUF 0.896, pLI 5.1228e-29, missense-Z -0.74532. *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):

- **hereditary breast carcinoma** — Refuted (AD)
- **Fanconi anemia complementation group P** — Definitive (AR)
- **familial ovarian cancer** — No Known Disease Relationship (AD)

## Protein context {#protein}

Residue **1726** lies in the 'interaction with plk1 and terf2-terf2ip' region; the 'disordered' region; the 'interaction with slx1' region.

AlphaFold model confidence (whole protein): pLDDT 47.20, 10% of residues very-high.

**7 experimental structure(s)** (PDB): [4M7C](https://www.rcsb.org/structure/4M7C), [4UYI](https://www.rcsb.org/structure/4UYI), [4ZOU](https://www.rcsb.org/structure/4ZOU), [7BU5](https://www.rcsb.org/structure/7BU5), [7TUJ](https://www.rcsb.org/structure/7TUJ), [9QED](https://www.rcsb.org/structure/9QED).

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

*Describes the biological roles of SLX4 (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:** SLX4's established molecular role includes enzyme activator activity. p.Ala1726Val falls in the interaction with plk1 and terf2-terf2ip region.


### Pathways affected {#pathways}

SLX4 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Fanconi Anemia Pathway](https://reactome.org/content/detail/R-HSA-6783310) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |

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

**Molecular function:** enzyme activator activity.

**Biological process:** double-strand break repair via homologous recombination, DNA repair, nucleotide-excision repair, DNA double-strand break processing involved in repair via single-strand annealing, positive regulation of telomere maintenance, telomeric D-loop disassembly.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-01-25.

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

**Submission history:** 5 submissions (2018–2025); 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 | 2018-01-12 |
| New York Genome Center | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-25 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-18 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-12-28 |

## Associated conditions {#conditions}

[Fanconi anemia](https://sugi.bio/atlas/disease/fanconi-anemia/), [Fanconi anemia complementation group P](https://sugi.bio/atlas/disease/fanconi-anemia-complementation-group-p/).

**Reported phenotype names (ClinVar):** Fanconi anemia, Fanconi anemia complementation group P, not specified, Fanconi's anemia, SLX4-Related Fanconi Anemia, AllHighlyPenetrant.

## Similar variants {#similar}

Related SLX4 variant pages (same residue, condition, or type): [SLX4 p.Ala1726=](/variant/slx4-p-ala1726), [SLX4 c.1684-1G>A](/variant/slx4-c-1684-minus-1g-a), [SLX4 c.951-1G>T](/variant/slx4-c-951-minus-1g-t), [SLX4 p.Arg1666Ter](/variant/slx4-p-arg1666ter), [SLX4 p.Arg481Ter](/variant/slx4-p-arg481ter), [SLX4 p.Arg713Ter](/variant/slx4-p-arg713ter), [SLX4 p.Gln1201Ter](/variant/slx4-p-gln1201ter), [SLX4 p.Gln1306Ter](/variant/slx4-p-gln1306ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 843315). 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.*