Is APOA1 p.Pro145= (c.435G>C) pathogenic?

APOA1 p.Pro145= (c.435G>C) is classified Likely benign in APOA1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-25). Ultra-rare (popmax 0.0493%, mid); Associated with Cardiovascular phenotype.

What condition is associated with APOA1 p.Pro145= (c.435G>C)?

APOA1 p.Pro145= (c.435G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA1 p.Pro145= (c.435G>C) in the general population?

APOA1 p.Pro145= (c.435G>C) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

APOA1 p.Pro145=

c.435G>C · rs759104683 · VCV1634611

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.9	GERP -2.7
Overall
CADD	9.289	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00459% 74/1,613,510 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
Admixed American	0.0167%	6,000
South Asian	0.00659%	15,182
European (non-Finnish)	0.00424%	23,601
African / African-American	0.004%	24,979
Remaining individualsnot grpmax-eligible	0.0032%	31,240

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.Pro145=
Coding: c.435G>C
MANE Select: NM_000039
dbSNP: rs759104683
Type: single nucleotide variant
Location: chr11:116836177 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB
Residue 145: 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)

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.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
APOA1 p.Arg34Gly 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-pro145 (accessed [today's date]).

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