Is MAPT p.Pro693Ala (c.2077C>G) pathogenic?

MAPT p.Pro693Ala (c.2077C>G) is classified Likely pathogenic in MAPT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-27). AlphaMissense: likely pathogenic (0.5856); Absent from gnomAD v4.1; Associated with supranuclear palsy, progressive, 1.

What condition is associated with MAPT p.Pro693Ala (c.2077C>G)?

MAPT p.Pro693Ala (c.2077C>G) is associated with supranuclear palsy, progressive, 1 (ClinVar).

How common is MAPT p.Pro693Ala (c.2077C>G) in the general population?

MAPT p.Pro693Ala (c.2077C>G) is absent from gnomAD v4.1 (gnomAD).

How is Progressive supranuclear palsy inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MAPT p.Pro693Ala (c.2077C>G)?

AlphaMissense predicts likely pathogenic (score 0.5856) — an in-silico prediction, not a clinical call.

MAPT p.Pro693Ala

c.2077C>G · rs63751438 · VCV3075676

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5856 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

supranuclear palsy, progressive, 1

Computational evidence

Protein change
AlphaMissense	0.5856	likely pathogenic ✓ concordant with ClinVar
REVEL	0.766	pathogenic-leaning
SaProt	LLR -11.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 14 kb · p 0.016 · regional, not allelic
Overall
CADD	26.3	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 P618A vs ClinVar P693A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAPT
Protein: p.Pro693Ala
Coding: c.2077C>G
MANE Select: NM_001377265
dbSNP: rs63751438
Type: single nucleotide variant
Location: chr17:46010388 (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

supranuclear palsy, progressive, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Progressive supranuclear palsy (Orphanet):

Inheritance: Not applicable
Onset: Adult, Elderly
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

MAPT p.Pro693Leu Pathogenic ★★ same residue
MAPT p.Pro693Ser Likely pathogenic ★★ same residue
MAPT p.Pro693= Likely benign ★★ same residue
MAPT p.Pro693Arg Uncertain significance ★ ⚠ same residue
MAPT p.Arg798Trp Pathogenic ★★ ⚠ same condition
MAPT p.Arg603Cys Uncertain significance ★★ ⚠ same condition
MAPT p.Lys456Glu Uncertain significance ★★ ⚠ same condition
MAPT p.Pro4Thr Uncertain significance ★★ ⚠ 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-pro693ala (accessed [today's date]).

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