Is APOA1 p.Pro28Arg (c.83C>G) pathogenic?

APOA1 p.Pro28Arg (c.83C>G) is classified Uncertain significance in APOA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-28). AlphaMissense: likely benign (0.1229); Ultra-rare (popmax 0.0165%, mid); Associated with hypoalphalipoproteinemia, primary, 2.

What condition is associated with APOA1 p.Pro28Arg (c.83C>G)?

APOA1 p.Pro28Arg (c.83C>G) is associated with hypoalphalipoproteinemia, primary, 2, hypoalphalipoproteinemia, primary, 2, intermediate, amyloidosis, hereditary systemic 3 (ClinVar).

How common is APOA1 p.Pro28Arg (c.83C>G) in the general population?

APOA1 p.Pro28Arg (c.83C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Apolipoprotein A-I deficiency inherited?

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

What do computational predictors say about APOA1 p.Pro28Arg (c.83C>G)?

AlphaMissense predicts likely benign (score 0.1229) — an in-silico prediction, not a clinical call.

APOA1 p.Pro28Arg

c.83C>G · rs121912721 · VCV17915

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1229 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypoalphalipoproteinemia, primary, 2

Computational evidence

Protein change
AlphaMissense	0.1229	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.68	GERP -0.68, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 1,576 bp · p 0.87 · regional, not allelic
Overall
CADD	12.45	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00421% 68/1,613,616 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
European (non-Finnish)	0.00534%	18,727
Remaining individualsnot grpmax-eligible	0.0048%	20,820
African / African-American	0.00133%	74,928

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.Pro28Arg
Coding: c.83C>G
dbSNP: rs121912721
Type: single nucleotide variant
Location: chr11:116837118 (GRCh38)

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

Disease context

hypoalphalipoproteinemia, primary, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Apolipoprotein A-I deficiency (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

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-pro28arg (accessed [today's date]).

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