Is MAPT p.Pro59Leu (c.176C>T) pathogenic?

MAPT p.Pro59Leu (c.176C>T) is classified Conflicting classifications of pathogenicity in MAPT (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-14). AlphaMissense: likely benign (0.0803); Rare (popmax 0.165%, amr); Associated with frontotemporal dementia.

What condition is associated with MAPT p.Pro59Leu (c.176C>T)?

MAPT p.Pro59Leu (c.176C>T) is associated with frontotemporal dementia (ClinVar).

How common is MAPT p.Pro59Leu (c.176C>T) in the general population?

MAPT p.Pro59Leu (c.176C>T) is rare (popmax 0.165%, amr) (gnomAD).

What do computational predictors say about MAPT p.Pro59Leu (c.176C>T)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

MAPT p.Pro59Leu

c.176C>T · rs143138715 · VCV1169744

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontotemporal dementia

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.19	GERP -0.28
Regional constraint	o/e 0.90	unconstrained · MANE · 29 kb · p 0.0043 · regional, not allelic
Overall
CADD	19.53	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.165% Admixed American · 99/60,020 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.129%

Overall 0.00793% 128/1,614,108 alleles · rare exomes 119/1,461,824 · genomes 9/152,284 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.165%	606
European (non-Finnish)	0.0022%	45,385
South Asian	0.0022%	45,538
African / African-American	0.00133%	75,062

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.Pro59Leu
Coding: c.176C>T
MANE Select: NM_001377265
dbSNP: rs143138715
Type: single nucleotide variant
Location: chr17:45971901 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 59: the 'disordered' region

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.Pro59= Likely benign ★ 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-pro59leu (accessed [today's date]).

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