# NM_006306.4(SMC1A):c.2691A>G (p.Lys897=)

https://sugi.bio/variant/smc1a-p-lys897

## Summary

**SMC1A p.Lys897= (c.2691A>G)** is classified **Benign/Likely benign** in SMC1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-09). Ultra-rare (popmax 0.0109%, nfe); Associated with Cornelia de Lange syndrome 2.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs782574044 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0109%, nfe)

## For patients & families {#patients}

This is a change in the SMC1A gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Cornelia de Lange syndrome 2.

*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/0015259/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SMC1A](https://sugi.bio/atlas/gene/SMC1A/) |
| Protein change (HGVS p.) | p.Lys897= |
| Coding change (HGVS c.) | c.2691A>G |
| MANE Select transcript | [NM_006306](https://www.ncbi.nlm.nih.gov/nuccore/NM_006306) |
| dbSNP | [rs782574044](https://www.ncbi.nlm.nih.gov/snp/rs782574044/) |
| Variant type | single nucleotide variant |
| Location | chrX:53396489-53396489 (GRCh38) |
| ClinVar | [VCV759135](https://www.ncbi.nlm.nih.gov/clinvar/variation/759135/) |

**All HGVS expressions:** `LRG_773:g.31182A>G`, `LRG_773t1:c.2625A>G`, `LRG_773t2:c.2691A>G`, `NC_000023.10:g.53423409T>C`, `NC_000023.11:g.53396489T>C`, `NG_006988.2:g.31182A>G`, `NM_001281463.1:c.2625A>G`, `NM_006306.4:c.2691A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.803, GERP 1.71, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.316**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.01**.
- Population frequency (gnomAD v4.1): grpmax **0.0109%** (nfe) · FAF95 0.00919% · FAF99 0.00844% · 98/895,023 in the highest group · 101/1,208,972 alleles overall — ultra-rare (popmax 0.0109%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0109% | 9,133 |
| Admixed American | 0.00439% | 22,773 |
| Remaining individuals (not grpmax-eligible) | 0.0021% | 47,572 |

*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}

**SMC1A** population constraint: 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):

- **X-linked complex neurodevelopmental disorder** — Definitive (XL)

## Protein context {#protein}

Residue **897** lies in an α-helix; a UniProt-annotated variant site (in dee85).

AlphaFold model confidence (whole protein): pLDDT 83.02, 23% of residues very-high.

**18 experimental structure(s)** (PDB): [6WG3](https://www.rcsb.org/structure/6WG3), [6WG4](https://www.rcsb.org/structure/6WG4), [6WG6](https://www.rcsb.org/structure/6WG6), [6WGE](https://www.rcsb.org/structure/6WGE), [7W1M](https://www.rcsb.org/structure/7W1M), [8P0A](https://www.rcsb.org/structure/8P0A).

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

*Describes the biological roles of SMC1A (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:** SMC1A's established molecular role includes chromatin binding.


### Pathways affected {#pathways}

SMC1A participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cohesin Loading onto Chromatin](https://reactome.org/content/detail/R-HSA-2470946) | curated |
| [Establishment of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2468052) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Meiotic synapsis](https://reactome.org/content/detail/R-HSA-1221632) | electronic |

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

**Molecular function:** chromatin binding, RNA binding, protein heterodimerization activity.

**Biological process:** sister chromatid cohesion, response to radiation, response to DNA damage checkpoint signaling, mitotic spindle assembly.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-09.

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

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-09-09 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-28 |

## Associated conditions {#conditions}

[Cornelia de Lange syndrome 2](https://sugi.bio/atlas/disease/cornelia-de-lange-syndrome-2/).

**Reported phenotype names (ClinVar):** Congenital muscular hypertrophy-cerebral syndrome, not specified, AllHighlyPenetrant, Cornelia de Lange syndrome 2, SMC1A-Related Cornelia de Lange Syndrome.

## Similar variants {#similar}

Related SMC1A variant pages (same residue, condition, or type): [SMC1A c.1114-2A>G](/variant/smc1a-c-1114-minus-2a-g), [SMC1A c.1546-2A>C](/variant/smc1a-c-1546-minus-2a-c), [SMC1A p.Arg1035Ter](/variant/smc1a-p-arg1035ter), [SMC1A p.Arg1049Gln](/variant/smc1a-p-arg1049gln), [SMC1A p.Arg1049Ter](/variant/smc1a-p-arg1049ter), [SMC1A p.Arg1066Cys](/variant/smc1a-p-arg1066cys), [SMC1A p.Arg1066His](/variant/smc1a-p-arg1066his), [SMC1A p.Arg171Ter](/variant/smc1a-p-arg171ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 759135). 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.*