MAPT p.Leu658=
c.1974G>A · rs373081497 · VCV323647
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
rare (popmax 0.429%, sas)
Conditions
2
MAPT-Related Spectrum Disorders
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 4.8 | GERP 4.7, phastCons 1 |
| Overall | ||
| CADD | 12.91 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.429%
South Asian · 391/91,058 alleles
Filtering AF
0.394%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.38%
Overall
0.0255%
412/1,613,946 alleles · rare
exomes 390/1,461,640 · genomes 22/152,306 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.429% | 233 |
| Remaining individualsnot grpmax-eligible | 0.032% | 3,125 |
| European (non-Finnish) | 8.47e-05% | 1,179,944 |
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.Leu658=
- Coding
- c.1974G>A
- MANE Select
- NM_001377265
- dbSNP
- rs373081497
- Type
- single nucleotide variant
- Location
- chr17:45996640 (GRCh38)
- Gene constraint
- LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 49.56 · 299 PDB
- Residue 658
- a β-strand; the 'microtubule-binding domain' region
Similar variants
- MAPT p.Leu658Val Pathogenic ★★ ⚠ same residue
- MAPT p.Leu658Pro 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.Arg798Trp Pathogenic ★★ ⚠ same condition
- MAPT p.Asn671Lys Pathogenic ★★ ⚠ same condition
- MAPT p.Asn688= 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-leu658 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown