# NM_001042750.2(STAG2):c.1101T>C (p.Phe367=)

https://sugi.bio/variant/stag2-p-phe367

## Summary

**STAG2 p.Phe367= (c.1101T>C)** is classified **Benign/Likely benign** in STAG2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-19). Ultra-rare (popmax 0.0629%, eas); Associated with Mullegama-Klein-Martinez syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs190643141 · 4 submitters · 2 linked conditions · ultra-rare (popmax 0.0629%, eas)

## For patients & families {#patients}

This is a change in the STAG2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to Mullegama-Klein-Martinez 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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STAG2](https://sugi.bio/atlas/gene/STAG2/) |
| Protein change (HGVS p.) | p.Phe367= |
| Coding change (HGVS c.) | c.1101T>C |
| MANE Select transcript | [NM_001042750](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042750) |
| dbSNP | [rs190643141](https://www.ncbi.nlm.nih.gov/snp/rs190643141/) |
| Variant type | single nucleotide variant |
| Location | chrX:124051204-124051204 (GRCh38) |
| ClinVar | [VCV1612997](https://www.ncbi.nlm.nih.gov/clinvar/variation/1612997/) |

**All HGVS expressions:** `LRG_782:g.95645T>C`, `LRG_782t1:c.1101T>C`, `NC_000023.10:g.123185054T>C`, `NC_000023.11:g.124051204T>C`, `NG_033796.2:g.95645T>C`, `NM_001042749.2:c.1101T>C`, `NM_001042750.2:c.1101T>C`, `NM_001042751.2:c.1101T>C`, `NM_001282418.2:c.1101T>C`, `NM_001375366.1:c.1101T>C`, `NM_001375367.1:c.1101T>C`, `NM_001375368.1:c.1101T>C`, `NM_001375369.1:c.1101T>C`, `NM_001375370.1:c.1101T>C`, `NM_001375371.1:c.1101T>C`, `NM_001375372.1:c.1101T>C`, `NM_001375373.1:c.1101T>C`, `NM_001375374.1:c.1101T>C`, `NM_001375375.1:c.1101T>C`, `NM_001375376.1:c.1101T>C`, `NM_001375377.1:c.1101T>C`, `NM_006603.5:c.1101T>C`

## 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 1.065, GERP -4.2, phastCons 1 — weakly conserved position
- CADD: **PHRED 9.032**. 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 **0.0629%** (eas) · FAF95 0.0422% · FAF99 0.0354% · 21/33,378 in the highest group · 22/1,183,485 alleles overall — ultra-rare (popmax 0.0629%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0629% | 1,589 |
| Remaining individuals (not grpmax-eligible) | 0.00214% | 46,620 |

*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}

**STAG2** 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.*

## Protein context {#protein}

Residue **367** lies in the scd domain; a UniProt-annotated variant site (in hpe13 and mkms; patient cells show decreased protein abundance; increased sister chromatid cohesion); a UniProt-annotated variant site (in mkms); a UniProt-annotated variant site (in hpe13); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 80.07, 64% of residues very-high.

**10 experimental structure(s)** (PDB): [4PJU](https://www.rcsb.org/structure/4PJU), [4PJW](https://www.rcsb.org/structure/4PJW), [4PK7](https://www.rcsb.org/structure/4PK7), [6QNX](https://www.rcsb.org/structure/6QNX), [7ZJS](https://www.rcsb.org/structure/7ZJS), [8K4D](https://www.rcsb.org/structure/8K4D).

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

*Describes the biological roles of STAG2 (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}

STAG2 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}

**Biological process:** sister chromatid cohesion, mitotic spindle assembly.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-19.

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

**Submission history:** 4 submissions (2019–2025); 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 | 2021-09-17 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-02-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-19 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-01 |

## Associated conditions {#conditions}

[Mullegama-Klein-Martinez syndrome](https://sugi.bio/atlas/disease/mullegama-klein-martinez-syndrome/), [holoprosencephaly 13, X-linked](https://sugi.bio/atlas/disease/holoprosencephaly-13-x-linked/).

**Reported phenotype names (ClinVar):** Mullegama-Klein-Martinez syndrome, not provided, Holoprosencephaly 13, X-linked, STAG2-related disorder, STAG2-Related Disorders, NEURODEVELOPMENTAL DISORDER, X-LINKED, WITH CRANIOFACIAL ABNORMALITIES, none provided.

## Similar variants {#similar}

Related STAG2 variant pages (same residue, condition, or type): [STAG2 p.Arg1012Ter](/variant/stag2-p-arg1012ter), [STAG2 p.Arg1033Ter](/variant/stag2-p-arg1033ter), [STAG2 p.Ala787Gly](/variant/stag2-p-ala787gly), [STAG2 p.Ala787Thr](/variant/stag2-p-ala787thr), [STAG2 p.Asn261Ser](/variant/stag2-p-asn261ser), [STAG2 p.Met1180Val](/variant/stag2-p-met1180val), [STAG2 p.Thr379Ile](/variant/stag2-p-thr379ile), [STAG2 c.1417-39A>C](/variant/stag2-c-1417-minus-39a-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 2026-10-14); 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 1612997). 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.*