Is APOA1 p.Ser76Arg (c.228C>G) pathogenic?

APOA1 p.Ser76Arg (c.228C>G) is classified Uncertain significance in APOA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-18). AlphaMissense: likely pathogenic (0.6605); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with APOA1 p.Ser76Arg (c.228C>G)?

APOA1 p.Ser76Arg (c.228C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA1 p.Ser76Arg (c.228C>G) in the general population?

APOA1 p.Ser76Arg (c.228C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOA1 p.Ser76Arg (c.228C>G)?

AlphaMissense predicts likely pathogenic (score 0.6605) — an in-silico prediction, not a clinical call.

APOA1 p.Ser76Arg

c.228C>G · rs771919707 · VCV2233945

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6605 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6605	likely pathogenic
REVEL	0.267	benign-leaning
SaProt	LLR -7.10	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.057	GERP -1.1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,576 bp · p 0.87 · regional, not allelic
Overall
CADD	16.61	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.Ser76Arg
Coding: c.228C>G
MANE Select: NM_000039
dbSNP: rs771919707
Type: single nucleotide variant
Location: chr11:116836384 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB
Residue 76: 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)

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

Similar variants

APOA1 p.Ser76Asn Uncertain significance ★★ ⚠ same residue
APOA1 p.Ala176Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala176Val Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala204Val Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala218Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala256Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Arg140Leu Uncertain significance ★★ ⚠ same condition
APOA1 p.Arg175Gly 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-ser76arg (accessed [today's date]).

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