Is MAPT p.Arg586Cys (c.1756C>T) pathogenic?

MAPT p.Arg586Cys (c.1756C>T) is classified Uncertain significance in MAPT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: likely pathogenic (0.7242); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with MAPT p.Arg586Cys (c.1756C>T)?

MAPT p.Arg586Cys (c.1756C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MAPT p.Arg586Cys (c.1756C>T) in the general population?

MAPT p.Arg586Cys (c.1756C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about MAPT p.Arg586Cys (c.1756C>T)?

AlphaMissense predicts likely pathogenic (score 0.7242) — an in-silico prediction, not a clinical call.

MAPT p.Arg586Cys

c.1756C>T · VCV3543258

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7242	likely pathogenic
REVEL	0.11	moderately benign-leaning
SaProt	LLR -10.41	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.7	GERP 8, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 4,962 bp · p 8.2e-07 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R511C vs ClinVar R586C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,900 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,612,652 alleles · very rare exomes 8/1,460,540 · genomes 1/152,112 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,900
European (non-Finnish)	0.000678%	147,499

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.Arg586Cys
Coding: c.1756C>T
MANE Select: NM_001377265
Type: single nucleotide variant
Location: chr17:45996422 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 511 UniProt numbering: the 'disordered' 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.Arg586His Uncertain significance ★ ⚠ same residue
MAPT p.Arg586= 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-arg586cys (accessed [today's date]).

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