# NM_003011.4(SET):c.422A>G (p.Lys141Arg)

https://sugi.bio/variant/set-p-lys141arg

## Summary

**SET p.Lys141Arg (c.422A>G)** is classified **Uncertain significance** in SET (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-16). AlphaMissense: likely pathogenic (0.8882); Very rare (popmax 0.00167%, amr); Associated with intellectual disability, autosomal dominant 58.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the SET gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to intellectual disability, autosomal dominant 58.

*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/0016476/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SET](https://sugi.bio/atlas/gene/SET/) |
| Protein change (HGVS p.) | p.Lys141Arg |
| Coding change (HGVS c.) | c.422A>G |
| MANE Select transcript | [NM_003011](https://www.ncbi.nlm.nih.gov/nuccore/NM_003011) |
| Variant type | single nucleotide variant |
| Location | chr9:128692911-128692911 (GRCh38) |
| ClinVar | [VCV3899875](https://www.ncbi.nlm.nih.gov/clinvar/variation/3899875/) |

**All HGVS expressions:** `NC_000009.11:g.131455190A>G`, `NC_000009.12:g.128692911A>G`, `NG_030356.1:g.14257A>G`, `NM_001122821.2:c.461A>G`, `NM_001248000.2:c.395A>G`, `NM_001248001.2:c.389A>G`, `NM_001374326.1:c.461A>G`, `NM_003011.4:c.422A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8882)
- REVEL 0.656 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.503 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.93, GERP 2.04, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **K154R** vs ClinVar **K141R**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 29.7**. 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 0.25** across the covering region of the MANE Select transcript (128,689,644–128,693,904), spanning 4,260 bp — the region is depleted of missense variation. Chi-square p 5.8e-31. 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>C, Δ0.79 acceptor 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 **0.00167%** (amr) · 1/59,906 in the highest group · 1/1,606,302 alleles overall — very rare (popmax 0.00167%, amr).

*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}

**SET** population constraint: LOEUF 0.167, pLI 0.99973, missense-Z 3.2081; 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):

- **intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **154** lies in a cross-link site; a β-strand; the 'earmuff domain' region.

AlphaFold model confidence (whole protein): pLDDT 78.62, 58% of residues very-high.

**3 experimental structure(s)** (PDB): [2E50](https://www.rcsb.org/structure/2E50), [7MTO](https://www.rcsb.org/structure/7MTO), [9I15](https://www.rcsb.org/structure/9I15).

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

*Describes the biological roles of SET (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Condensation of Prophase Chromosomes](https://reactome.org/content/detail/R-HSA-2299718) | curated |
| [HuR (ELAVL1) binds and stabilizes mRNA](https://reactome.org/content/detail/R-HSA-450520) | curated |

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

**Biological process:** negative regulation of neuron apoptotic process, negative regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-16.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetics Department, Catlab | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-16 |

## Associated conditions {#conditions}

[intellectual disability, autosomal dominant 58](https://sugi.bio/atlas/disease/intellectual-disability-autosomal-dominant-58/).

**Reported phenotype names (ClinVar):** Intellectual disability, autosomal dominant 58, MENTAL RETARDATION, AUTOSOMAL DOMINANT 58, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 58.

## Same-residue context {#hotspot}

Residue **141** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SET p.Lys141fs](/variant/set-p-lys141fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SET variant pages (same residue, condition, or type): [SET p.Lys141fs](/variant/set-p-lys141fs), [SET c.663+5G>C](/variant/set-c-663-plus-5g-c), [SET p.His105Tyr](/variant/set-p-his105tyr), [SET p.Asp224Asn](/variant/set-p-asp224asn), [SET p.Asp260Glu](/variant/set-p-asp260glu), [SET p.Glu261Asp](/variant/set-p-glu261asp), [SET c.132-17C>T](/variant/set-c-132-minus-17c-t), [SET c.493-14C>T](/variant/set-c-493-minus-14c-t).

### 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 3899875). 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.*