# NM_001377265.1(MAPT):c.1564T>C (p.Ser522Pro)

https://sugi.bio/variant/mapt-p-ser522pro

## Summary

**MAPT p.Ser522Pro (c.1564T>C)** is classified **Benign** in MAPT (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.043); Common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with frontotemporal dementia.

**At a glance:** Benign · review: Multiple submitters · rsID rs10445337 · 9 submitters · 1 linked condition · AlphaMissense likely benign · common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the MAPT gene that is classified as benign — not considered disease-causing, submitted by 9 submitters, and is linked to frontotemporal dementia.

*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 | 146 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008436/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MAPT](https://sugi.bio/atlas/gene/MAPT/) |
| Protein change (HGVS p.) | p.Ser522Pro |
| Coding change (HGVS c.) | c.1564T>C |
| MANE Select transcript | [NM_001377265](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377265) |
| dbSNP | [rs10445337](https://www.ncbi.nlm.nih.gov/snp/rs10445337/) |
| Variant type | single nucleotide variant |
| Location | chr17:45990034-45990034 (GRCh38) |
| ClinVar | [VCV98203](https://www.ncbi.nlm.nih.gov/clinvar/variation/98203/) |

**All HGVS expressions:** `LRG_660:g.100572T>C`, `LRG_660t1:c.1339T>C`, `LRG_660t2:c.1564T>C`, `NC_000017.10:g.44067400T>C`, `NC_000017.11:g.45990034T>C`, `NG_007398.2:g.100572T>C`, `NM_001123066.4:c.1339T>C`, `NM_001123067.4:c.343-1426T>C`, `NM_001203251.2:c.343-1426T>C`, `NM_001203252.2:c.430-1426T>C`, `NM_001377265.1:c.1564T>C`, `NM_001377266.1:c.1408-1426T>C`, `NM_001377267.1:c.343-1426T>C`, `NM_001377268.1:c.256-1426T>C`, `NM_005910.6:c.430-1426T>C`, `NM_016834.5:c.256-1426T>C`, `NM_016835.5:c.1339T>C`, `NM_016841.5:c.256-1426T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.043)
- REVEL 0.064 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.266 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.262, GERP 2.75, phastCons 1 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S447P** vs ClinVar **S522P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 17.55**. 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 0.90** across the covering region of the MANE Select transcript (45,962,338–45,991,578), spanning 29,240 bp. Chi-square p 0.0043. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, T>G, IS in the release and scores Δ0.21 acceptor loss, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **22.1%** (nfe) · FAF95 22.1% · FAF99 22% · 261,331/1,179,830 in the highest group · 305,028/1,613,906 alleles overall — common (popmax 22.1%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 27.6% | 4 |
| Ashkenazi Jewish (not grpmax-eligible) | 25.4% | 4 |
| European (non-Finnish) (grpmax) | 22.1% | 5 |
| Middle Eastern | 20.3% | 5 |
| Remaining individuals (not grpmax-eligible) | 17.7% | 6 |
| Admixed American | 13.8% | 7 |
| South Asian | 7.93% | 13 |
| Finnish (not grpmax-eligible) | 7.12% | 14 |
| African / African-American | 4.64% | 22 |
| East Asian | 0.0958% | 1,044 |

Amish 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}

**MAPT** population constraint: LOEUF 0.723, pLI 2.1814e-05, missense-Z 2.4904; ClinGen dosage — haploinsufficiency 0/3, 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 **447** lies in a UniProt-annotated variant site (in); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 49.56, 0% of residues very-high.

**299 experimental structure(s)** (PDB): [10IJ](https://www.rcsb.org/structure/10IJ), [10IK](https://www.rcsb.org/structure/10IK), [1I8H](https://www.rcsb.org/structure/1I8H), [22JY](https://www.rcsb.org/structure/22JY), [28LJ](https://www.rcsb.org/structure/28LJ), [28LO](https://www.rcsb.org/structure/28LO) — incl. mutant structure 6GK7.

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

*Describes the biological roles of MAPT (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:** MAPT's established molecular role includes enzyme inhibitor activity. p.Ser522Pro falls in the disordered region.


### Pathways affected {#pathways}

MAPT participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Caspase-mediated cleavage of cytoskeletal proteins](https://reactome.org/content/detail/R-HSA-264870) | curated |
| [Activation of AMPK downstream of NMDARs](https://reactome.org/content/detail/R-HSA-9619483) | other |
| [PKR-mediated signaling](https://reactome.org/content/detail/R-HSA-9833482) | other |

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

**Molecular function:** enzyme inhibitor activity, microtubule binding, SH3 domain binding, enzyme binding, protein kinase binding, apolipoprotein binding.

**Biological process:** microtubule cytoskeleton organization, DNA damage response, synapse assembly, learning or memory, memory, regulation of autophagy.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-12.

**Submitter consensus:** conflicting (8 Benign, 1 not provided).

**Submission history:** 9 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| VIB  Department of Molecular Genetics, University of Antwerp | not provided | no classification provided | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Mendelics | Benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-08-11 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-12 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[frontotemporal dementia](https://sugi.bio/atlas/disease/frontotemporal-dementia/).

**Reported phenotype names (ClinVar):** Frontotemporal dementia, not provided, not specified, AllHighlyPenetrant, none provided, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), FRONTOTEMPORAL DEMENTIA WITH PARKINSONISM, FRONTOTEMPORAL LOBE DEMENTIA, MULTIPLE SYSTEM TAUOPATHY WITH PRESENILE DEMENTIA, Dementia, frontotemporal, with or without parkinsonism.

## Similar variants {#similar}

Related MAPT variant pages (same residue, condition, or type): [MAPT c.1999-10G>T](/variant/mapt-c-1999-minus-10g-t), [MAPT c.2091+16C>T](/variant/mapt-c-2091-plus-16c-t), [MAPT c.2091+3G>A](/variant/mapt-c-2091-plus-3g-a), [MAPT p.Arg798Trp](/variant/mapt-p-arg798trp), [MAPT p.Asn671Lys](/variant/mapt-p-asn671lys), [MAPT p.Asn688=](/variant/mapt-p-asn688), [MAPT p.Gln728His](/variant/mapt-p-gln728his), [MAPT p.Gly727Ser](/variant/mapt-p-gly727ser).

### 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 98203). 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.*