Is MAPT p.Arg613Trp (c.1837C>T) pathogenic?

MAPT p.Arg613Trp (c.1837C>T) is classified Uncertain significance in MAPT (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-05-03). AlphaMissense: likely pathogenic (0.8907); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with MAPT p.Arg613Trp (c.1837C>T)?

MAPT p.Arg613Trp (c.1837C>T) is associated with Inborn genetic diseases, frontotemporal dementia (ClinVar).

How common is MAPT p.Arg613Trp (c.1837C>T) in the general population?

MAPT p.Arg613Trp (c.1837C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about MAPT p.Arg613Trp (c.1837C>T)?

AlphaMissense predicts likely pathogenic (score 0.8907) — an in-silico prediction, not a clinical call.

MAPT p.Arg613Trp

c.1837C>T · rs374286863 · VCV2205337

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8907	likely pathogenic
REVEL	0.198	benign-leaning
SaProt	LLR -11.61	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 3.3	GERP 4.9, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 4,962 bp · p 8.2e-07 · regional, not allelic
Overall
CADD	28.2	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 R538W vs ClinVar R613W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,068 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00198% 32/1,613,414 alleles · very rare exomes 29/1,461,252 · genomes 3/152,162 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,356
European (non-Finnish)	0.00229%	43,700
Admixed American	0.00167%	59,994
African / African-American	0.00133%	74,928

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.Arg613Trp
Coding: c.1837C>T
MANE Select: NM_001377265
dbSNP: rs374286863
Type: single nucleotide variant
Location: chr17:45996503 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 538 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

Also linked: frontotemporal dementia

Similar variants

MAPT p.Arg613Gln 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
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-arg613trp (accessed [today's date]).

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