# NM_001080517.3(SETD5):c.1561_1564dup (p.Phe522fs)

https://sugi.bio/variant/setd5-p-phe522fs

## Summary

**SETD5 p.Phe522fs (c.1561_1564dup)** is classified **Pathogenic** in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-01). Associated with intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the SETD5 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017673/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SETD5](https://sugi.bio/atlas/gene/SETD5/) |
| Protein change (HGVS p.) | p.Phe522fs |
| Coding change (HGVS c.) | c.1561_1564dup |
| MANE Select transcript | [NM_001080517](https://www.ncbi.nlm.nih.gov/nuccore/NM_001080517) |
| Variant type | Duplication |
| Location | chr3:9447084-9447085 (GRCh38) |
| ClinVar | [VCV3764622](https://www.ncbi.nlm.nih.gov/clinvar/variation/3764622/) |

**All HGVS expressions:** `NC_000003.11:g.9488770_9488773dup`, `NC_000003.12:g.9447086_9447089dup`, `NG_034132.1:g.54387_54390dup`, `NM_001080517.3:c.1561_1564dup`, `NM_001292043.2:c.1267_1270dup`, `NM_001349451.2:c.1267_1270dup`

## 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 11.186, GERP 1.82, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.376, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 14 of 23**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**SETD5** population constraint: LOEUF 0.376, pLI 1, missense-Z 2.0399; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **syndromic complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **522** lies in the 'disordered' region; a UniProt-annotated variant site (in mrd23).

AlphaFold model confidence (whole protein): pLDDT 47.10, 8% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Daryl Scott Lab, Baylor College of Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-01 |

## Associated conditions {#conditions}

[intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency](https://sugi.bio/atlas/disease/intellectual-disability-facial-dysmorphism-syndrome-due-to-setd5-haploinsufficiency/).

**Reported phenotype names (ClinVar):** Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, Intellectual developmental disorder, autosomal dominant 23.

## Similar variants {#similar}

Related SETD5 variant pages (same residue, condition, or type): [SETD5 p.Tyr1000fs](/variant/setd5-p-tyr1000fs), [SETD5 p.Ala647fs](/variant/setd5-p-ala647fs), [SETD5 p.Asn1059fs](/variant/setd5-p-asn1059fs), [SETD5 p.Asn814fs](/variant/setd5-p-asn814fs), [SETD5 p.Gln534fs](/variant/setd5-p-gln534fs), [SETD5 p.Gln801fs](/variant/setd5-p-gln801fs), [SETD5 p.Gly344fs](/variant/setd5-p-gly344fs), [SETD5 p.His966fs](/variant/setd5-p-his966fs).

### 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 3764622). 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.*