Is MAPT p.Arg798Trp (c.2392C>T) pathogenic?

MAPT p.Arg798Trp (c.2392C>T) is classified Pathogenic in MAPT (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-10-07). AlphaMissense: ambiguous (0.5455); Very rare (popmax 0.00186%, nfe); Associated with frontotemporal dementia.

What condition is associated with MAPT p.Arg798Trp (c.2392C>T)?

MAPT p.Arg798Trp (c.2392C>T) is associated with frontotemporal dementia, late-onset Parkinson disease, Pick disease (ClinVar).

How common is MAPT p.Arg798Trp (c.2392C>T) in the general population?

MAPT p.Arg798Trp (c.2392C>T) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about MAPT p.Arg798Trp (c.2392C>T)?

AlphaMissense predicts ambiguous (score 0.5455) — an in-silico prediction, not a clinical call.

MAPT p.Arg798Trp

c.2392C>T · rs63750424 · VCV14247

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

ambiguous

0.5455 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

frontotemporal dementia

Computational evidence

Protein change
AlphaMissense	0.5455	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -14.54	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.63	GERP 1.2, phastCons 0.089
Regional constraint	o/e 0.52	unconstrained · MANE · 9,855 bp · p 4.8e-09 · regional, not allelic
Overall
CADD	23.9	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 R723W vs ClinVar R798W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00186% European (non-Finnish) · 22/1,180,014 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,614,132 alleles · very rare exomes 24/1,461,828 · genomes 0/152,304 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	32,000
European (non-Finnish)grpmax	0.00186%	53,637

Finnish shows a higher raw frequency than the grpmax group above it. 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.

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.Arg798Trp
Coding: c.2392C>T
MANE Select: NM_001377265
dbSNP: rs63750424
Type: single nucleotide variant
Location: chr17:46024061 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 723 UniProt numbering: a UniProt-annotated variant site (in ftd1/alzheimer disease; accelerates aggregation of tau into filaments; reduces tau phosphorylation in cells compared to both the wild-type and other mutant forms); a β-strand; the 'disordered' 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.Arg798Pro 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.Asn671Lys Pathogenic ★★ ⚠ same condition
MAPT p.Asn688= Pathogenic ★★ same condition
MAPT p.Gln728His Pathogenic/Likely pathogenic ★★ ⚠ same condition
MAPT p.Gly727Ser Pathogenic/Likely 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-arg798trp (accessed [today's date]).

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