Is MAPT p.Ser348Pro (c.1042T>C) pathogenic?

MAPT p.Ser348Pro (c.1042T>C) is classified Uncertain significance in MAPT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-08-14). AlphaMissense: likely benign (0.0667); Very rare (popmax 0.00602%, nfe); Associated with late-onset Parkinson disease.

What condition is associated with MAPT p.Ser348Pro (c.1042T>C)?

MAPT p.Ser348Pro (c.1042T>C) is associated with late-onset Parkinson disease, Pick disease, progressive supranuclear palsy-parkinsonism syndrome (ClinVar).

How common is MAPT p.Ser348Pro (c.1042T>C) in the general population?

MAPT p.Ser348Pro (c.1042T>C) is very rare (popmax 0.00602%, nfe) (gnomAD).

How is Hereditary late-onset Parkinson disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MAPT p.Ser348Pro (c.1042T>C)?

AlphaMissense predicts likely benign (score 0.0667) — an in-silico prediction, not a clinical call.

MAPT p.Ser348Pro

c.1042T>C · rs753640366 · VCV452810

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00602%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

late-onset Parkinson disease

Computational evidence

Protein change
AlphaMissense	0.0667	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -5.73	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 -0.33	GERP -4
Regional constraint	o/e 0.90	unconstrained · MANE · 29 kb · p 0.0043 · regional, not allelic
Overall
CADD	6.661	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 S273P vs ClinVar S348P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00602% European (non-Finnish) · 71/1,179,956 alleles

Filtering AF 0.00486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00447%

Overall 0.00477% 77/1,613,294 alleles · very rare exomes 73/1,461,390 · genomes 4/151,904 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00602%	16,619
Admixed American	0.005%	19,999
African / African-American	0.00267%	37,404
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Ser348Pro
Coding: c.1042T>C
MANE Select: NM_001377265
dbSNP: rs753640366
Type: single nucleotide variant
Location: chr17:45983621 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 273 UniProt numbering: the 'disordered' region

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

Disease context

late-onset Parkinson disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Pick disease progressive supranuclear palsy-parkinsonism syndrome supranuclear palsy, progressive, 1 frontotemporal dementia

For Hereditary late-onset Parkinson disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

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
MAPT p.Gly727Ser 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-ser348pro (accessed [today's date]).

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