# NM_001377265.1(MAPT):c.2079G>A (p.Pro693=)

https://sugi.bio/variant/mapt-p-pro693

## Summary

**MAPT p.Pro693= (c.2079G>A)** is classified **Likely benign** in MAPT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-24). Ultra-rare (popmax 0.0575%, eas); Associated with MAPT-Related Spectrum Disorders.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs63751395 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.0575%, eas)

## For patients & families {#patients}

This is a change in the MAPT gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to MAPT-Related Spectrum Disorders.

*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 | [MAPT](https://sugi.bio/atlas/gene/MAPT/) |
| Protein change (HGVS p.) | p.Pro693= |
| Coding change (HGVS c.) | c.2079G>A |
| MANE Select transcript | [NM_001377265](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377265) |
| dbSNP | [rs63751395](https://www.ncbi.nlm.nih.gov/snp/rs63751395/) |
| Variant type | single nucleotide variant |
| Location | chr17:46010390-46010390 (GRCh38) |
| ClinVar | [VCV98216](https://www.ncbi.nlm.nih.gov/clinvar/variation/98216/) |

**All HGVS expressions:** `LRG_660:g.120928G>A`, `LRG_660t1:c.1854G>A`, `LRG_660t2:c.2079G>A`, `NC_000017.10:g.44087756G>A`, `NC_000017.11:g.46010390G>A`, `NG_007398.2:g.120928G>A`, `NM_001123066.4:c.1908G>A`, `NM_001123067.4:c.816G>A`, `NM_001203251.2:c.736-3853G>A`, `NM_001203252.2:c.823-3853G>A`, `NM_001377265.1:c.2079G>A`, `NM_001377266.1:c.1801-3853G>A`, `NM_001377267.1:c.736-3853G>A`, `NM_001377268.1:c.649-3853G>A`, `NM_005910.6:c.903G>A`, `NM_016834.5:c.729G>A`, `NM_016835.5:c.1854G>A`, `NM_016841.5:c.649-3853G>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 -0.442, GERP -7.19, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 11.48**. 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: **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). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. 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. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. 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, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MAPT (1,198 scored positions, the nearest 2 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *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 **0.0575%** (eas) · FAF95 0.0399% · FAF99 0.0342% · 25/43,450 in the highest group · 70/1,574,224 alleles overall — ultra-rare (popmax 0.0575%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0575% | 1,738 |
| African / African-American | 0.0336% | 2,977 |
| Middle Eastern | 0.0334% | 2,996 |
| South Asian | 0.0035% | 28,554 |
| Remaining individuals (not grpmax-eligible) | 0.00327% | 30,543 |
| Admixed American | 0.00185% | 53,920 |
| Finnish (not grpmax-eligible) | 0.00163% | 61,336 |
| European (non-Finnish) | 0.000949% | 105,323 |

*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 **693** lies in a β-strand.

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.


### 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-10-24.

**Submitter consensus:** conflicting (2 Likely benign, 1 not provided).

**Submission history:** 3 submissions (2017–2022); 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 |  |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-10-24 |

## Associated conditions {#conditions}

[MAPT-Related Spectrum Disorders](https://sugi.bio/atlas/disease/mapt-related-spectrum-disorders/), [frontotemporal dementia](https://sugi.bio/atlas/disease/frontotemporal-dementia/).

**Reported phenotype names (ClinVar):** MAPT-Related Spectrum Disorders, not provided, Frontotemporal dementia, 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, WILHELMSEN-LYNCH DISEASE.

## Same-residue context {#hotspot}

Residue **693** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [MAPT p.Pro693Leu](/variant/mapt-p-pro693leu), [MAPT p.Pro693Ser](/variant/mapt-p-pro693ser), [MAPT p.Pro693Ala](/variant/mapt-p-pro693ala). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MAPT variant pages (same residue, condition, or type): [MAPT p.Pro693Leu](/variant/mapt-p-pro693leu), [MAPT p.Pro693Ser](/variant/mapt-p-pro693ser), [MAPT p.Pro693Arg](/variant/mapt-p-pro693arg), [MAPT p.Pro693Ala](/variant/mapt-p-pro693ala), [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).

### 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 98216). 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.*