Is MAPT p.Ile784Val (c.2350A>G) pathogenic?

MAPT p.Ile784Val (c.2350A>G) is classified Uncertain significance in MAPT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-17). AlphaMissense: likely pathogenic (0.7778); Very rare (popmax 0.000424%, nfe); Associated with Early-onset dementia of unclear type.

What condition is associated with MAPT p.Ile784Val (c.2350A>G)?

MAPT p.Ile784Val (c.2350A>G) is associated with Early-onset dementia of unclear type, frontotemporal dementia (ClinVar).

How common is MAPT p.Ile784Val (c.2350A>G) in the general population?

MAPT p.Ile784Val (c.2350A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about MAPT p.Ile784Val (c.2350A>G)?

AlphaMissense predicts likely pathogenic (score 0.7778) — an in-silico prediction, not a clinical call.

MAPT p.Ile784Val

c.2350A>G · rs991713081 · VCV870547

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Early-onset dementia of unclear type

Computational evidence

Protein change
AlphaMissense	0.7778	likely pathogenic
REVEL	0.211	benign-leaning
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 7.2, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 9,855 bp · p 4.8e-09 · regional, not allelic
Overall
CADD	26.2	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 I709V vs ClinVar I784V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,016 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,614,088 alleles · very rare exomes 7/1,461,844 · genomes 0/152,244 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)grpmax	0.000424%	236,003

Remaining individuals 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.Ile784Val
Coding: c.2350A>G
MANE Select: NM_001377265
dbSNP: rs991713081
Type: single nucleotide variant
Location: chr17:46024019 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 709 UniProt numbering: a β-strand

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

Disease context

Early-onset dementia of unclear type

Also linked: frontotemporal dementia

Similar variants

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
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-ile784val (accessed [today's date]).

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