Is MAPT p.Val729Ala (c.2186T>C) pathogenic?

MAPT p.Val729Ala (c.2186T>C) is classified Uncertain significance in MAPT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely pathogenic (0.9724); Absent from gnomAD v4.1.

How common is MAPT p.Val729Ala (c.2186T>C) in the general population?

MAPT p.Val729Ala (c.2186T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPT p.Val729Ala (c.2186T>C)?

AlphaMissense predicts likely pathogenic (score 0.9724) — an in-silico prediction, not a clinical call.

MAPT p.Val729Ala

c.2186T>C · VCV3363784

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9724 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9724	likely pathogenic · top 9% in MAPT
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -13.03	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 7.9	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	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 V654A vs ClinVar V729A) — 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.Val729Ala
Coding: c.2186T>C
MANE Select: NM_001377265
Type: single nucleotide variant
Location: chr17:46018630 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 654 UniProt numbering: a UniProt-annotated variant site (in ftd1; ultrastructural and biochemical characteristics indistinguishable from alzheimer disease; accelerates aggregation of tau into filaments); a β-strand; the 'microtubule-binding domain' region

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

Similar variants

MAPT p.Val729Met Pathogenic ★★ same residue
MAPT c.1999-10G>T Pathogenic ★★ same type
MAPT c.2091+16C>T Pathogenic ★★ same type
MAPT c.2091+3G>A Pathogenic ★★ same type
MAPT p.Arg798Trp Pathogenic ★★ ⚠ same type
MAPT p.Asn671Lys Pathogenic ★★ ⚠ same type
MAPT p.Asn688= Pathogenic ★★ same type
MAPT p.Gln728His Pathogenic/Likely pathogenic ★★ ⚠ same type

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-val729ala (accessed [today's date]).

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