Is MAPT p.Arg297Ser (c.889C>A) pathogenic?

MAPT p.Arg297Ser (c.889C>A) is classified Uncertain significance in MAPT (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-10-09). AlphaMissense: likely benign (0.2376); Rare (popmax 0.232%, mid); Associated with multiple system atrophy.

What condition is associated with MAPT p.Arg297Ser (c.889C>A)?

MAPT p.Arg297Ser (c.889C>A) is associated with multiple system atrophy, Pick disease, frontotemporal dementia (ClinVar).

How common is MAPT p.Arg297Ser (c.889C>A) in the general population?

MAPT p.Arg297Ser (c.889C>A) is rare (popmax 0.232%, mid) (gnomAD).

How is Multiple system atrophy inherited?

Typically Multigenic/multifactorial, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MAPT p.Arg297Ser (c.889C>A)?

AlphaMissense predicts likely benign (score 0.2376) — an in-silico prediction, not a clinical call.

MAPT p.Arg297Ser

c.889C>A · rs150983093 · VCV638372

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2376 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.232%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple system atrophy

Computational evidence

Protein change
AlphaMissense	0.2376	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -5.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 5.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 29 kb · p 0.0043 · regional, not allelic
Overall
CADD	21.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R222S vs ClinVar R297S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.232% Middle Eastern · 14/6,024 alleles

Filtering AF 0.141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.113%

Overall 0.0273% 439/1,608,098 alleles · rare exomes 367/1,455,840 · genomes 72/152,258 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.232%	430
African / African-American	0.112%	892
Remaining individualsnot grpmax-eligible	0.0804%	1,244
Admixed American	0.0585%	1,709
European (non-Finnish)	0.0215%	4,651
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,406
South Asian	0.0022%	45,365

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.Arg297Ser
Coding: c.889C>A
MANE Select: NM_001377265
dbSNP: rs150983093
Type: single nucleotide variant
Location: chr17:45983468 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 222 UniProt numbering: the 'disordered' region

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

Disease context

multiple system atrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Pick disease frontotemporal dementia

For Multiple system atrophy (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MAPT p.Arg297Cys Likely benign ★ 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-arg297ser (accessed [today's date]).

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