Is MAPT p.Pro693Ser (c.2077C>T) pathogenic?

MAPT p.Pro693Ser (c.2077C>T) is classified Likely pathogenic in MAPT (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-28). AlphaMissense: likely pathogenic (0.9433); No allele count reported in gnomAD v4.1 (AN 1,575,410); Associated with frontotemporal dementia.

What condition is associated with MAPT p.Pro693Ser (c.2077C>T)?

MAPT p.Pro693Ser (c.2077C>T) is associated with frontotemporal dementia (ClinVar).

How common is MAPT p.Pro693Ser (c.2077C>T) in the general population?

MAPT p.Pro693Ser (c.2077C>T) is no allele count reported in gnomAD v4.1 (AN 1,575,410) (gnomAD).

What do computational predictors say about MAPT p.Pro693Ser (c.2077C>T)?

AlphaMissense predicts likely pathogenic (score 0.9433) — an in-silico prediction, not a clinical call.

MAPT p.Pro693Ser

c.2077C>T · rs63751438 · VCV14256

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9433 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,575,410)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontotemporal dementia

Computational evidence

Protein change
AlphaMissense	0.9433	likely pathogenic ✓ concordant with ClinVar
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -12.34	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	27.6	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 P618S vs ClinVar P693S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,575,410). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MAPT
Protein: p.Pro693Ser
Coding: c.2077C>T
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

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

Similar variants

MAPT p.Pro693Leu Pathogenic ★★ same residue
MAPT p.Pro693= Likely benign ★★ same residue
MAPT p.Pro693Arg Uncertain significance ★ ⚠ same residue
MAPT p.Pro693Ala Likely pathogenic ★ 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-pro693ser (accessed [today's date]).

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