# NM_001197104.2(KMT2A):c.135G>A (p.Pro45=)

https://sugi.bio/variant/kmt2a-p-pro45

## Summary

**KMT2A p.Pro45= (c.135G>A)** is classified **Benign/Likely benign** in KMT2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-31). Rare (popmax 0.456%, sas); Associated with Wiedemann-Steiner syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs9332746 · 4 submitters · 1 linked condition · rare (popmax 0.456%, sas)

## For patients & families {#patients}

This is a change in the KMT2A gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to Wiedemann-Steiner syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005565/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [KMT2A](https://sugi.bio/atlas/gene/KMT2A/) |
| Protein change (HGVS p.) | p.Pro45= |
| Coding change (HGVS c.) | c.135G>A |
| MANE Select transcript | [NM_001197104](https://www.ncbi.nlm.nih.gov/nuccore/NM_001197104) |
| dbSNP | [rs9332746](https://www.ncbi.nlm.nih.gov/snp/rs9332746/) |
| Variant type | single nucleotide variant |
| Location | chr11:118436647-118436647 (GRCh38) |
| ClinVar | [VCV1566281](https://www.ncbi.nlm.nih.gov/clinvar/variation/1566281/) |

**All HGVS expressions:** `LRG_613:g.5158G>A`, `NC_000011.10:g.118436647G>A`, `NC_000011.9:g.118307362G>A`, `NG_027813.1:g.5158G>A`, `NM_001197104.1:c.135G>A`, `NM_001197104.2:c.135G>A`, `NM_005933.4:c.135G>A`

## Computational & population evidence {#evidence}

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

- **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 3.901, GERP 0.649, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.57**. 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.*
- 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 **0.456%** (sas) · FAF95 0.385% · FAF99 0.358% · 103/22,588 in the highest group · 134/1,115,862 alleles overall — rare (popmax 0.456%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.456% | 219 |
| Remaining individuals (not grpmax-eligible) | 0.0416% | 2,403 |
| Middle Eastern | 0.0362% | 2,762 |
| European (non-Finnish) | 0.00155% | 64,596 |

*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}

**KMT2A** population constraint: LOEUF 0.065, pLI 1, missense-Z 8.7941; ClinGen dosage — haploinsufficiency 3, 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):

- **Wiedemann-Steiner syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **45** lies in the 'disordered' region.

**60 experimental structure(s)** (PDB): [2AGH](https://www.rcsb.org/structure/2AGH), [2J2S](https://www.rcsb.org/structure/2J2S), [2JYI](https://www.rcsb.org/structure/2JYI), [2KKF](https://www.rcsb.org/structure/2KKF), [2KU7](https://www.rcsb.org/structure/2KU7), [2KYU](https://www.rcsb.org/structure/2KYU) — incl. mutant structure 9C4S.

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

*Describes the biological roles of KMT2A (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:** KMT2A's established molecular role includes zinc ion binding. p.Pro45= falls in the disordered region.


### Pathways affected {#pathways}

KMT2A participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of WDR5-containing histone-modifying complexes](https://reactome.org/content/detail/R-HSA-9772755) | curated |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes](https://reactome.org/content/detail/R-HSA-9931510) | electronic |
| [Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters](https://reactome.org/content/detail/R-HSA-9931512) | electronic |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | electronic |
| [The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex](https://reactome.org/content/detail/R-HSA-9931521) | electronic |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |

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

**Molecular function:** zinc ion binding, histone H3K4 methyltransferase activity, identical protein binding, protein homodimerization activity, unmethylated CpG binding, protein-cysteine methyltransferase activity.

**Biological process:** T-helper 2 cell differentiation, transcription initiation-coupled chromatin remodeling, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II, protein-containing complex assembly, negative regulation of DNA methylation-dependent heterochromatin formation.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-31.

**Submitter consensus:** conflicting (3 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-03-23 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-01-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-08-31 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-19 |

## Associated conditions {#conditions}

[Wiedemann-Steiner syndrome](https://sugi.bio/atlas/disease/wiedemann-steiner-syndrome/).

**Reported phenotype names (ClinVar):** Wiedemann-Steiner syndrome, not provided, KMT2A-related disorder, not specified, AllHighlyPenetrant, none provided, Growth deficiency and mental retardation with facial dysmorphism, KMT2A-related condition.

## Same-residue context {#hotspot}

Residue **45** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [KMT2A p.Pro45fs](/variant/kmt2a-p-pro45fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related KMT2A variant pages (same residue, condition, or type): [KMT2A p.Pro45Ser](/variant/kmt2a-p-pro45ser), [KMT2A p.Pro45fs](/variant/kmt2a-p-pro45fs), [KMT2A p.Pro45Arg](/variant/kmt2a-p-pro45arg), [KMT2A p.Pro45Thr](/variant/kmt2a-p-pro45thr), [KMT2A c.11071+1G>A](/variant/kmt2a-c-11071-plus-1g-a), [KMT2A c.4012+1G>C](/variant/kmt2a-c-4012-plus-1g-c), [KMT2A c.502+1G>A](/variant/kmt2a-c-502-plus-1g-a), [KMT2A c.6079+2T>C](/variant/kmt2a-c-6079-plus-2t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1566281). 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.*