Is MAPT p.Arg5Cys (c.13C>T) pathogenic?

MAPT p.Arg5Cys (c.13C>T) is classified Conflicting classifications of pathogenicity in MAPT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-06-27). AlphaMissense: ambiguous (0.3732); Very rare (popmax 0.00446%, eas); Associated with MAPT-Related Spectrum Disorders.

What condition is associated with MAPT p.Arg5Cys (c.13C>T)?

MAPT p.Arg5Cys (c.13C>T) is associated with MAPT-Related Spectrum Disorders, frontotemporal dementia (ClinVar).

How common is MAPT p.Arg5Cys (c.13C>T) in the general population?

MAPT p.Arg5Cys (c.13C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about MAPT p.Arg5Cys (c.13C>T)?

AlphaMissense predicts ambiguous (score 0.3732) — an in-silico prediction, not a clinical call.

MAPT p.Arg5Cys

c.13C>T · rs766166210 · VCV889714

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

MAPT-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.3732	ambiguous
REVEL	0.192	benign-leaning
SaProt	LLR -7.35	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 4.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 29 kb · p 0.0043 · regional, not allelic
Overall
CADD	24.5	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 0.00446% East Asian · 2/44,866 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000496% 8/1,611,978 alleles · very rare exomes 8/1,459,852 · genomes 0/152,126 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,433
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.0011%	90,962
European (non-Finnish)	0.000339%	294,954

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.Arg5Cys
Coding: c.13C>T
MANE Select: NM_001377265
dbSNP: rs766166210
Type: single nucleotide variant
Location: chr17:45962350 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 5: a UniProt-annotated variant site (in ftd1; reduces the ability of tau to promote microtubule assembly and promotes fibril formation in vitro); a UniProt-annotated variant site (in psnp1; delays assembly initiation and lowers the mass of microtubules formed; but the assembly rate is increased compared to normal tau); the 'disordered' region

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

Disease context

MAPT-Related Spectrum Disorders

Also linked: frontotemporal dementia

Similar variants

MAPT p.Arg5His Conflicting classifications of pathogenicity ★ ⚠ same residue
MAPT p.Arg5Leu Pathogenic ⚠ 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-arg5cys (accessed [today's date]).

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