Is MAPT p.Ser627= (c.1881G>A) pathogenic?

MAPT p.Ser627= (c.1881G>A) is classified Likely benign in MAPT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-13). Ultra-rare (popmax 0.0495%, mid); Associated with frontotemporal dementia.

What condition is associated with MAPT p.Ser627= (c.1881G>A)?

MAPT p.Ser627= (c.1881G>A) is associated with frontotemporal dementia, late-onset Parkinson disease, Pick disease (ClinVar).

How common is MAPT p.Ser627= (c.1881G>A) in the general population?

MAPT p.Ser627= (c.1881G>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

MAPT p.Ser627=

c.1881G>A · rs115142761 · VCV1126880

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Conditions

frontotemporal dementia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -10
Overall
CADD	3.349	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00744%

Overall 0.0075% 121/1,613,352 alleles · ultra-rare exomes 114/1,461,186 · genomes 7/152,166 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
European (non-Finnish)	0.00941%	10,628
African / African-American	0.008%	12,500
South Asian	0.0011%	90,978

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.Ser627=
Coding: c.1881G>A
MANE Select: NM_001377265
dbSNP: rs115142761
Type: single nucleotide variant
Location: chr17:45996547 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 627: an α-helix; the 'microtubule-binding domain' 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

Also linked: late-onset Parkinson disease Pick disease progressive supranuclear palsy-parkinsonism syndrome supranuclear palsy, progressive, 1

Similar variants

MAPT p.Ser627Leu 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-ser627 (accessed [today's date]).

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