Is APOA1 p.Leu165Pro (c.494T>C) pathogenic?

APOA1 p.Leu165Pro (c.494T>C) is classified Uncertain significance in APOA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: likely pathogenic (0.9868); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with APOA1 p.Leu165Pro (c.494T>C)?

APOA1 p.Leu165Pro (c.494T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA1 p.Leu165Pro (c.494T>C) in the general population?

APOA1 p.Leu165Pro (c.494T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOA1 p.Leu165Pro (c.494T>C)?

AlphaMissense predicts likely pathogenic (score 0.9868) — an in-silico prediction, not a clinical call.

APOA1 p.Leu165Pro

c.494T>C · rs779081481 · VCV2586722

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9868 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,612,346)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9868	likely pathogenic · top 1% in APOA1
REVEL	0.707	pathogenic-leaning
SaProt	LLR -14.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,576 bp · p 0.87 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,612,346). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: APOA1
Protein: p.Leu165Pro
Coding: c.494T>C
MANE Select: NM_000039
dbSNP: rs779081481
Type: single nucleotide variant
Location: chr11:116836118 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB
Residue 165: 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.Leu165Arg Pathogenic ★ 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-leu165pro (accessed [today's date]).

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