Is MAPT p.Val692Ile (c.2074G>A) pathogenic?

MAPT p.Val692Ile (c.2074G>A) is classified Benign/Likely benign in MAPT (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-15). AlphaMissense: likely benign (0.0887); Rare (popmax 0.369%, afr); Associated with supranuclear palsy, progressive, 1.

What condition is associated with MAPT p.Val692Ile (c.2074G>A)?

MAPT p.Val692Ile (c.2074G>A) is associated with supranuclear palsy, progressive, 1, late-onset Parkinson disease, Pick disease (ClinVar).

How common is MAPT p.Val692Ile (c.2074G>A) in the general population?

MAPT p.Val692Ile (c.2074G>A) is rare (popmax 0.369%, afr) (gnomAD).

How is Progressive supranuclear palsy inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MAPT p.Val692Ile (c.2074G>A)?

AlphaMissense predicts likely benign (score 0.0887) — an in-silico prediction, not a clinical call.

MAPT p.Val692Ile

c.2074G>A · rs116733906 · VCV1271108

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0887 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.369%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

supranuclear palsy, progressive, 1

Computational evidence

Protein change
AlphaMissense	0.0887	likely benign
REVEL	0.475	indeterminate
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 5.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 14 kb · p 0.016 · regional, not allelic
Overall
CADD	22.2	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 V617I vs ClinVar V692I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.369% African / African-American · 275/74,508 alleles

Filtering AF 0.333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.319%

Overall 0.0205% 323/1,576,696 alleles · rare exomes 159/1,424,424 · genomes 164/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.369%	271
Remaining individualsnot grpmax-eligible	0.0392%	2,549
Admixed American	0.0221%	4,523
Middle Eastern	0.0167%	5,980
East Asian	0.00687%	14,551
South Asian	0.00233%	42,905
European (non-Finnish)	0.000517%	193,327

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.Val692Ile
Coding: c.2074G>A
MANE Select: NM_001377265
dbSNP: rs116733906
Type: single nucleotide variant
Location: chr17:46010385 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 617 UniProt numbering: a UniProt-annotated variant site (in); the 'microtubule-binding domain' region

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

Disease context

supranuclear palsy, progressive, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: late-onset Parkinson disease Pick disease progressive supranuclear palsy-parkinsonism syndrome frontotemporal dementia

For Progressive supranuclear palsy (Orphanet):

Inheritance: Not applicable
Onset: Adult, Elderly
Prevalence: 1-9 / 100 000 (Worldwide)

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-val692ile (accessed [today's date]).

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