Is MAPT p.Pro693Leu (c.2078C>T) pathogenic?

MAPT p.Pro693Leu (c.2078C>T) is classified Pathogenic in MAPT (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-03). AlphaMissense: likely pathogenic (0.9637); Very rare (popmax 0.000259%, nfe); Associated with frontotemporal dementia.

What condition is associated with MAPT p.Pro693Leu (c.2078C>T)?

MAPT p.Pro693Leu (c.2078C>T) is associated with frontotemporal dementia, late-onset Parkinson disease, Pick disease (ClinVar).

How common is MAPT p.Pro693Leu (c.2078C>T) in the general population?

MAPT p.Pro693Leu (c.2078C>T) is very rare (popmax 0.000259%, nfe) (gnomAD).

What do computational predictors say about MAPT p.Pro693Leu (c.2078C>T)?

AlphaMissense predicts likely pathogenic (score 0.9637) — an in-silico prediction, not a clinical call.

MAPT p.Pro693Leu

c.2078C>T · rs63751273 · VCV14245

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9637 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000259%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontotemporal dementia

Computational evidence

Protein change
AlphaMissense	0.9637	likely pathogenic ✓ concordant with ClinVar · top 10% in MAPT
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -13.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 7.2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 14 kb · p 0.016 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P618L vs ClinVar P693L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000259% European (non-Finnish) · 3/1,158,538 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000191% 3/1,574,190 alleles · very rare exomes 3/1,421,918 · genomes 0/152,272 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MAPT
Protein: p.Pro693Leu
Coding: c.2078C>T
MANE Select: NM_001377265
dbSNP: rs63751273
Type: single nucleotide variant
Location: chr17:46010389 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 618 UniProt numbering: a UniProt-annotated variant site (in ftd1; most common mutation; reduction in the ability to promote microtubule assembly; accelerates aggregation of tau into filaments); a UniProt-annotated variant site (in ftd1 and cbd; reduction in the ability to promote microtubule assembly); a β-strand; the 'microtubule-binding domain' region

Full MAPT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

frontotemporal dementia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: late-onset Parkinson disease Pick disease progressive supranuclear palsy-parkinsonism syndrome supranuclear palsy, progressive, 1

Similar variants

MAPT p.Pro693Ser Likely pathogenic ★★ same residue
MAPT p.Pro693= Likely benign ★★ same residue
MAPT p.Pro693Ala Likely pathogenic ★ same residue
MAPT p.Pro693Arg Uncertain significance ★ ⚠ same residue
MAPT c.1999-10G>T Pathogenic ★★ same condition
MAPT c.2091+16C>T Pathogenic ★★ same condition
MAPT c.2091+3G>A Pathogenic ★★ same condition
MAPT p.Arg798Trp Pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mapt-p-pro693leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown