Is MAPT p.Ser712Phe (c.2135C>T) pathogenic?

MAPT p.Ser712Phe (c.2135C>T) is classified Pathogenic in MAPT (ClinVar, Single submitter, 3 submitters; last evaluated 2018-01-22). AlphaMissense: likely pathogenic (0.9966); Absent from gnomAD v4.1; Associated with frontotemporal dementia.

What condition is associated with MAPT p.Ser712Phe (c.2135C>T)?

MAPT p.Ser712Phe (c.2135C>T) is associated with frontotemporal dementia, Pick disease (ClinVar).

How common is MAPT p.Ser712Phe (c.2135C>T) in the general population?

MAPT p.Ser712Phe (c.2135C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPT p.Ser712Phe (c.2135C>T)?

AlphaMissense predicts likely pathogenic (score 0.9966) — an in-silico prediction, not a clinical call.

MAPT p.Ser712Phe

c.2135C>T · rs63750635 · VCV14262

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9966 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontotemporal dementia

Computational evidence

Protein change
AlphaMissense	0.9966	likely pathogenic ✓ concordant with ClinVar · top 2% in MAPT
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -13.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 7.2, 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 S637F vs ClinVar S712F) — 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.Ser712Phe
Coding: c.2135C>T
MANE Select: NM_001377265
dbSNP: rs63750635
Type: single nucleotide variant
Location: chr17:46014286 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 637 UniProt numbering: a UniProt-annotated variant site (in pidb; markedly reduced ability of tau to promote microtubule assembly); a β-strand; 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: Pick disease

Similar variants

MAPT p.Ser712= 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-ser712phe (accessed [today's date]).

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