Is APOA1 p.Ser166Arg (c.498C>A) pathogenic?

APOA1 p.Ser166Arg (c.498C>A) is classified Conflicting classifications of pathogenicity in APOA1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.2701); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOA1 p.Ser166Arg (c.498C>A)?

APOA1 p.Ser166Arg (c.498C>A) is associated with Cardiovascular phenotype, familial visceral amyloidosis, hypoalphalipoproteinemia, primary, 1 (ClinVar).

How common is APOA1 p.Ser166Arg (c.498C>A) in the general population?

APOA1 p.Ser166Arg (c.498C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about APOA1 p.Ser166Arg (c.498C>A)?

AlphaMissense predicts likely benign (score 0.2701) — an in-silico prediction, not a clinical call.

APOA1 p.Ser166Arg

c.498C>A · rs757899657 · VCV302503

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2701	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -4.69	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 -0.015	GERP 0.19
Regional constraint	o/e 1.01	unconstrained · MANE · 1,576 bp · p 0.87 · regional, not allelic
Overall
CADD	13.36	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

Grpmax group 0.00133% African / African-American · 1/74,944 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00397% 64/1,611,734 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.152%	658
Remaining individualsnot grpmax-eligible	0.00961%	10,409
African / African-Americangrpmax	0.00133%	74,944
South Asian	0.0011%	91,078
European (non-Finnish)	0.000932%	107,267

Ashkenazi Jewish 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: APOA1
Protein: p.Ser166Arg
Coding: c.498C>A
MANE Select: NM_000039
dbSNP: rs757899657
Type: single nucleotide variant
Location: chr11:116836114 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB
Residue 166: 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); a UniProt-annotated variant site (in fha2; missing protein expression); an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial visceral amyloidosis hypoalphalipoproteinemia, primary, 1 hypoalphalipoproteinemia, primary, 2 hypoalphalipoproteinemia, primary, 2, intermediate amyloidosis, hereditary systemic 3

Similar variants

APOA1 p.Ser166Asn Uncertain significance ★ ⚠ same residue
APOA1 p.Ser166Gly Uncertain significance ★ ⚠ same residue
APOA1 p.Ser166Thr Uncertain significance ★ ⚠ same residue
APOA1 p.Gln23Ter Pathogenic ★★ same condition
APOA1 p.Gly50Arg Pathogenic ★★ same condition
APOA1 c.-21+22G>A Uncertain significance ★★ same condition
APOA1 p.Ala176Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala176Val 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-ser166arg (accessed [today's date]).

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