Is APOA1 p.Arg34Gly (c.100C>G) pathogenic?

APOA1 p.Arg34Gly (c.100C>G) is classified Uncertain significance in APOA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.3939); Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOA1 p.Arg34Gly (c.100C>G)?

APOA1 p.Arg34Gly (c.100C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA1 p.Arg34Gly (c.100C>G) in the general population?

APOA1 p.Arg34Gly (c.100C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about APOA1 p.Arg34Gly (c.100C>G)?

AlphaMissense predicts ambiguous (score 0.3939) — an in-silico prediction, not a clinical call.

APOA1 p.Arg34Gly

c.100C>G · rs1373700967 · VCV2578141

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3939	ambiguous
REVEL	0.263	benign-leaning
SaProt	LLR -7.48	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.1, phastCons 0.62
Regional constraint	o/e 1.01	unconstrained · MANE · 1,576 bp · p 0.87 · regional, not allelic
Overall
CADD	21.0	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 0.000169% European (non-Finnish) · 2/1,179,964 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,860 alleles · very rare

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.Arg34Gly
Coding: c.100C>G
MANE Select: NM_000039
dbSNP: rs1373700967
Type: single nucleotide variant
Location: chr11:116837101 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB
Residue 34: a UniProt-annotated variant site (in fha2; no protein expression); a UniProt-annotated variant site (in baltimore); 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

Similar variants

APOA1 p.Arg34= Likely benign ★★ same residue
APOA1 p.Arg34Leu Uncertain significance ★★ ⚠ same residue
APOA1 p.Arg34Ter Pathogenic ★ same residue
APOA1 p.Arg34Gln 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

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-arg34gly (accessed [today's date]).

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