Is MAPT p.Leu658Pro (c.1973T>C) pathogenic?

MAPT p.Leu658Pro (c.1973T>C) is classified Uncertain significance in MAPT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-29). AlphaMissense: likely pathogenic (0.9982); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MAPT p.Leu658Pro (c.1973T>C)?

MAPT p.Leu658Pro (c.1973T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MAPT p.Leu658Pro (c.1973T>C) in the general population?

MAPT p.Leu658Pro (c.1973T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPT p.Leu658Pro (c.1973T>C)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

MAPT p.Leu658Pro

c.1973T>C · VCV3543261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic · top 1% in MAPT
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -12.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 8.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 14 kb · p 0.016 · 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 L583P vs ClinVar L658P) — 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.Leu658Pro
Coding: c.1973T>C
MANE Select: NM_001377265
Type: single nucleotide variant
Location: chr17:45996639 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 583 UniProt numbering: a UniProt-annotated variant site (in ftd1; less able to promote microtubule assembly than wild-type tau); the 'microtubule-binding domain' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAPT p.Leu658Val Pathogenic ★★ ⚠ same residue
MAPT p.Leu658= Benign/Likely benign ★★ same residue
MAPT p.Ala818Thr Uncertain significance ★★ ⚠ same condition
MAPT p.Arg613Trp Uncertain significance ★★ ⚠ same condition
MAPT p.Asp465Gly Uncertain significance ★★ ⚠ same condition
MAPT c.2091+29G>A Benign/Likely benign ★★ same condition
MAPT c.220+2451C>A Uncertain significance ★ ⚠ same condition
MAPT p.Arg547Trp Uncertain significance ★ ⚠ 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-leu658pro (accessed [today's date]).

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