Is MAPT p.Ser697Ile (c.2090G>T) pathogenic?

MAPT p.Ser697Ile (c.2090G>T) is classified Uncertain significance in MAPT (ClinVar, Single submitter, 2 submitters; last evaluated 2020-09-18). AlphaMissense: likely pathogenic (0.6954); Absent from gnomAD v4.1.

How common is MAPT p.Ser697Ile (c.2090G>T) in the general population?

MAPT p.Ser697Ile (c.2090G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPT p.Ser697Ile (c.2090G>T)?

AlphaMissense predicts likely pathogenic (score 0.6954) — an in-silico prediction, not a clinical call.

MAPT p.Ser697Ile

c.2090G>T · rs63751165 · VCV1256161

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6954 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6954	likely pathogenic
REVEL	0.256	benign-leaning
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.5	GERP 4.7, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 3,912 bp · p 2.5e-06 · regional, not allelic
Overall
CADD	33.0	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 S622I vs ClinVar S697I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAPT
Protein: p.Ser697Ile
Coding: c.2090G>T
MANE Select: NM_001377265
dbSNP: rs63751165
Type: single nucleotide variant
Location: chr17:46010401 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 622 UniProt numbering: a UniProt-annotated variant site (in ftd1; minimal parkinsonism; very early age of onset); the 'microtubule-binding domain' region; a modified residue (phosphoserine; by phk)

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

Similar variants

MAPT p.Ser697= Pathogenic/Likely pathogenic ★★ same residue
MAPT p.Ser697Asn Pathogenic ★ ⚠ same residue
MAPT c.1999-10G>T Pathogenic ★★ same type
MAPT c.2091+16C>T Pathogenic ★★ same type
MAPT c.2091+3G>A Pathogenic ★★ same type
MAPT p.Arg798Trp Pathogenic ★★ ⚠ same type
MAPT p.Asn671Lys Pathogenic ★★ ⚠ same type
MAPT p.Asn688= Pathogenic ★★ same type

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-ser697ile (accessed [today's date]).

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