Is MAPT p.Ser502Phe (c.1505C>T) pathogenic?

MAPT p.Ser502Phe (c.1505C>T) is classified Benign/Likely benign in MAPT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.2146); Rare (popmax 0.218%, nfe); Associated with frontotemporal dementia.

What condition is associated with MAPT p.Ser502Phe (c.1505C>T)?

MAPT p.Ser502Phe (c.1505C>T) is associated with frontotemporal dementia (ClinVar).

How common is MAPT p.Ser502Phe (c.1505C>T) in the general population?

MAPT p.Ser502Phe (c.1505C>T) is rare (popmax 0.218%, nfe) (gnomAD).

What do computational predictors say about MAPT p.Ser502Phe (c.1505C>T)?

AlphaMissense predicts likely benign (score 0.2146) — an in-silico prediction, not a clinical call.

MAPT p.Ser502Phe

c.1505C>T · rs143956882 · VCV460294

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2146 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.218%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontotemporal dementia

Computational evidence

Protein change
AlphaMissense	0.2146	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -9.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.1	GERP 5.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 29 kb · p 0.0043 · regional, not allelic
Overall
CADD	25.4	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 S427F vs ClinVar S502F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.218% European (non-Finnish) · 2,577/1,180,020 alleles

Filtering AF 0.211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.208%

Overall 0.191% 3,089/1,614,206 alleles · rare exomes 2,849/1,461,870 · genomes 240/152,336 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.25%	400
European (non-Finnish)grpmax	0.218%	458
Remaining individualsnot grpmax-eligible	0.208%	481
Admixed American	0.19%	527
Ashkenazi Jewishnot grpmax-eligible	0.125%	800
Middle Eastern	0.0495%	2,021
South Asian	0.0439%	2,277
African / African-American	0.036%	2,780
East Asian	0.00223%	44,888

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser502Phe
Coding: c.1505C>T
MANE Select: NM_001377265
dbSNP: rs143956882
Type: single nucleotide variant
Location: chr17:45989975 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 427 UniProt numbering: the 'disordered' 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

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-ser502phe (accessed [today's date]).

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