Is APOA1 p.Trp96Arg (c.286T>C) pathogenic?

APOA1 p.Trp96Arg (c.286T>C) is classified Pathogenic in APOA1 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.8657); Absent from gnomAD v4.1; Associated with amyloidosis, hereditary systemic 3.

What condition is associated with APOA1 p.Trp96Arg (c.286T>C)?

APOA1 p.Trp96Arg (c.286T>C) is associated with amyloidosis, hereditary systemic 3 (ClinVar).

How common is APOA1 p.Trp96Arg (c.286T>C) in the general population?

APOA1 p.Trp96Arg (c.286T>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary ATTR amyloidosis inherited?

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

What do computational predictors say about APOA1 p.Trp96Arg (c.286T>C)?

AlphaMissense predicts likely pathogenic (score 0.8657) — an in-silico prediction, not a clinical call.

APOA1 p.Trp96Arg

c.286T>C · VCV4812879

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8657 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

amyloidosis, hereditary systemic 3

Computational evidence

Protein change
AlphaMissense	0.8657	likely pathogenic ✓ concordant with ClinVar
REVEL	0.354	indeterminate
SaProt	LLR -2.96	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 3.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,576 bp · p 0.87 · regional, not allelic
Overall
CADD	19.08	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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: APOA1
Protein: p.Trp96Arg
Coding: c.286T>C
MANE Select: NM_000039
Type: single nucleotide variant
Location: chr11:116836326 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB
Residue 96: the '10 x approximate tandem repeats' region; a UniProt-annotated variant site (in fha2; no protein expression); a UniProt-annotated variant site (in hdl deficiency; with periorbital xanthelasmas; decreased protein abundance); an α-helix

Full APOA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amyloidosis, hereditary systemic 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary ATTR amyloidosis (Orphanet):

Inheritance: Autosomal dominant
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

APOA1 p.Gly50Arg Pathogenic ★★ same condition
APOA1 c.-21+22G>A Uncertain significance ★★ same condition
APOA1 p.Ala220Pro Uncertain significance ★★ ⚠ same condition
APOA1 p.Arg34Leu Uncertain significance ★★ ⚠ same condition
APOA1 p.Glu170Lys Uncertain significance ★★ ⚠ same condition
APOA1 p.Glu171Val Uncertain significance ★★ ⚠ same condition
APOA1 p.Glu222Lys Uncertain significance ★★ ⚠ same condition
APOA1 p.His179Gln Uncertain significance ★★ ⚠ 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/apoa1-p-trp96arg (accessed [today's date]).

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