# NM_020998.4(MST1):c.1533C>T (p.Ser511=)

https://sugi.bio/variant/mst1-p-ser511

## Summary

**MST1 p.Ser511= (c.1533C>T)** is classified **Benign/Likely benign** in MST1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-01). Rare (popmax 0.25%, amr).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs149138392 · 3 submitters · rare (popmax 0.25%, amr)

## For patients & families {#patients}

This is a change in the MST1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [MST1](https://sugi.bio/atlas/gene/MST1/) |
| Protein change (HGVS p.) | p.Ser511= |
| Coding change (HGVS c.) | c.1533C>T |
| MANE Select transcript | [NM_020998](https://www.ncbi.nlm.nih.gov/nuccore/NM_020998) |
| dbSNP | [rs149138392](https://www.ncbi.nlm.nih.gov/snp/rs149138392/) |
| Variant type | single nucleotide variant |
| Location | chr3:49685273-49685273 (GRCh38) |
| ClinVar | [VCV721569](https://www.ncbi.nlm.nih.gov/clinvar/variation/721569/) |

**All HGVS expressions:** `NC_000003.11:g.49722706G>A`, `NC_000003.12:g.49685273G>A`, `NG_011438.1:g.16272G>A`, `NG_011603.1:g.717G>A`, `NG_016454.1:g.8491C>T`, `NM_001393581.1:c.1529C>T`, `NM_001393582.1:c.1533C>T`, `NM_001393583.1:c.1403C>T`, `NM_001393584.1:c.1398C>T`, `NM_001393585.1:c.1233C>T`, `NM_020998.4:c.1533C>T`, `NR_146060.2:n.2316C>T`

## 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 2.968, GERP -3.71, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.74**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.28 donor 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 **0.25%** (amr) · FAF95 0.227% · FAF99 0.224% · 150/60,016 in the highest group · 3,651/1,613,368 alleles overall — rare (popmax 0.25%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 1.66% | 60 |
| Remaining individuals (not grpmax-eligible) | 0.274% | 365 |
| Admixed American (grpmax) | 0.25% | 400 |
| European (non-Finnish) | 0.234% | 427 |
| Finnish (not grpmax-eligible) | 0.0709% | 1,410 |
| Middle Eastern | 0.033% | 3,028 |
| African / African-American | 0.0253% | 3,950 |
| South Asian | 0.0132% | 7,589 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


Curated gene–disease validity (ClinGen):

- **combined immunodeficiency due to STK4 deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.45, 49% of residues very-high.

**16 experimental structure(s)** (PDB): [2JO8](https://www.rcsb.org/structure/2JO8), [3COM](https://www.rcsb.org/structure/3COM), [4NR2](https://www.rcsb.org/structure/4NR2), [4OH8](https://www.rcsb.org/structure/4OH8), [5TWG](https://www.rcsb.org/structure/5TWG), [5TWH](https://www.rcsb.org/structure/5TWH).

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

*Describes the biological roles of MST1 (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:** MST1's established molecular role includes magnesium ion binding.


### Pathways affected {#pathways}

MST1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Signaling by Hippo](https://reactome.org/content/detail/R-HSA-2028269) | curated |

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

**Molecular function:** magnesium ion binding, protein kinase activity, protein serine/threonine kinase activity, ATP binding, identical protein binding, protein homodimerization activity.

**Biological process:** cell morphogenesis, positive regulation of protein phosphorylation, protein phosphorylation, protein import into nucleus, apoptotic process, peptidyl-serine phosphorylation.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-01.

**Submitter consensus:** conflicting (2 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2019–2026); 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 | 2019-12-31 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related MST1 variant pages (same residue, condition, or type): [STK4 p.Arg115Ter](/variant/stk4-p-arg115ter), [STK4 p.Arg117Ter](/variant/stk4-p-arg117ter), [STK4 p.Arg148Ter](/variant/stk4-p-arg148ter), [STK4 p.Arg245Ter](/variant/stk4-p-arg245ter), [STK4 p.Ala391Val](/variant/stk4-p-ala391val), [STK4 p.Ala479Ser](/variant/stk4-p-ala479ser), [STK4 p.Arg310Gln](/variant/stk4-p-arg310gln), [STK4 p.Arg310Pro](/variant/stk4-p-arg310pro).

### 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 721569). 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.*