Is MAPT p.Arg613Gln (c.1838G>A) pathogenic?

MAPT p.Arg613Gln (c.1838G>A) is classified Uncertain significance in MAPT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-26). AlphaMissense: likely pathogenic (0.5671); Very rare (popmax 0.000883%, nfe); Associated with frontotemporal dementia.

What condition is associated with MAPT p.Arg613Gln (c.1838G>A)?

MAPT p.Arg613Gln (c.1838G>A) is associated with frontotemporal dementia (ClinVar).

How common is MAPT p.Arg613Gln (c.1838G>A) in the general population?

MAPT p.Arg613Gln (c.1838G>A) is very rare (popmax 0.000883%, nfe) (gnomAD).

What do computational predictors say about MAPT p.Arg613Gln (c.1838G>A)?

AlphaMissense predicts likely pathogenic (score 0.5671) — an in-silico prediction, not a clinical call.

MAPT p.Arg613Gln

c.1838G>A · rs779901466 · VCV2138061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000883%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontotemporal dementia

Computational evidence

Protein change
AlphaMissense	0.5671	likely pathogenic
REVEL	0.178	moderately benign-leaning
SaProt	LLR -4.36	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.4	GERP 5.9, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 4,962 bp · p 8.2e-07 · regional, not allelic
Overall
CADD	29.3	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 R538Q vs ClinVar R613Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000883% European (non-Finnish) · 9/1,018,848 alleles

Filtering AF 0.000416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000301%

Overall 0.000794% 11/1,385,232 alleles · very rare exomes 11/1,238,742 · genomes 0/146,490 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00207%	48,346
Remaining individualsnot grpmax-eligible	0.00197%	50,888
European (non-Finnish)grpmax	0.000883%	113,205

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg613Gln
Coding: c.1838G>A
MANE Select: NM_001377265
dbSNP: rs779901466
Type: single nucleotide variant
Location: chr17:45996504 (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

frontotemporal dementia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAPT p.Arg613Trp 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-arg613gln (accessed [today's date]).

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