Is MAPT p.Thr69Ala (c.205A>G) pathogenic?

MAPT p.Thr69Ala (c.205A>G) is classified Uncertain significance in MAPT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-21). AlphaMissense: likely benign (0.141); Very rare (popmax 0.000848%, nfe); Associated with MAPT-related disorder.

What condition is associated with MAPT p.Thr69Ala (c.205A>G)?

MAPT p.Thr69Ala (c.205A>G) is associated with MAPT-related disorder (ClinVar).

How common is MAPT p.Thr69Ala (c.205A>G) in the general population?

MAPT p.Thr69Ala (c.205A>G) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about MAPT p.Thr69Ala (c.205A>G)?

AlphaMissense predicts likely benign (score 0.141) — an in-silico prediction, not a clinical call.

MAPT p.Thr69Ala

c.205A>G · rs778599496 · VCV2628522

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MAPT-related disorder

Computational evidence

Protein change
AlphaMissense	0.141	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -6.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.3	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 29 kb · p 0.0043 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000848% European (non-Finnish) · 10/1,179,934 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,613,836 alleles · very rare exomes 10/1,461,748 · genomes 0/152,088 · joint denominator

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.Thr69Ala
Coding: c.205A>G
MANE Select: NM_001377265
dbSNP: rs778599496
Type: single nucleotide variant
Location: chr17:45971930 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 69: a modified residue (phosphothreonine); the 'disordered' region

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

Disease context

MAPT-related disorder

Similar variants

MAPT p.Asn671Lys Pathogenic ★★ ⚠ same condition
MAPT p.Ile784Val Uncertain significance ★★ ⚠ same condition
MAPT c.220+2450A>G Likely benign ★★ same condition
MAPT c.-133C>A Benign ★★ same condition
MAPT c.-13A>G Benign ★★ same condition
MAPT c.-285A>G Benign ★★ same condition
MAPT c.*1067T>C Benign ★★ same condition
MAPT c.*1101A>G Benign ★★ 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-thr69ala (accessed [today's date]).

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