Is MAPT p.Lys709Thr (c.2126A>C) pathogenic?

MAPT p.Lys709Thr (c.2126A>C) is classified Uncertain significance in MAPT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely pathogenic (0.7917); Absent from gnomAD v4.1; Associated with frontotemporal dementia.

What condition is associated with MAPT p.Lys709Thr (c.2126A>C)?

MAPT p.Lys709Thr (c.2126A>C) is associated with frontotemporal dementia (ClinVar).

How common is MAPT p.Lys709Thr (c.2126A>C) in the general population?

MAPT p.Lys709Thr (c.2126A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPT p.Lys709Thr (c.2126A>C)?

AlphaMissense predicts likely pathogenic (score 0.7917) — an in-silico prediction, not a clinical call.

MAPT p.Lys709Thr

c.2126A>C · VCV3654589

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7917 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

frontotemporal dementia

Computational evidence

Protein change
AlphaMissense	0.7917	likely pathogenic
REVEL	0.538	indeterminate
SaProt	LLR -11.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 7.2, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 3,912 bp · p 2.5e-06 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM K634T vs ClinVar K709T) — 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.Lys709Thr
Coding: c.2126A>C
MANE Select: NM_001377265
Type: single nucleotide variant
Location: chr17:46014277 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 634 UniProt numbering: a cross-link site; a UniProt-annotated variant site (in ftd1); a β-strand; a functional site (not glycated); the 'microtubule-binding domain' region; a modified residue (n6-acetyllysine; alternate)

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.Lys709Met 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
MAPT p.Asn671Lys Pathogenic ★★ ⚠ same condition
MAPT p.Asn688= Pathogenic ★★ same condition
MAPT p.Gln728His 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-lys709thr (accessed [today's date]).

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