Is APOA1 p.Phe95Leu (c.283T>C) pathogenic?

APOA1 p.Phe95Leu (c.283T>C) is classified Uncertain significance in APOA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-02). AlphaMissense: likely pathogenic (0.919); Absent from gnomAD v4.1.

How common is APOA1 p.Phe95Leu (c.283T>C) in the general population?

APOA1 p.Phe95Leu (c.283T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOA1 p.Phe95Leu (c.283T>C)?

AlphaMissense predicts likely pathogenic (score 0.919) — an in-silico prediction, not a clinical call.

APOA1 p.Phe95Leu

c.283T>C · rs2134231444 · VCV1172844

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.919 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.919	likely pathogenic · top 8% in APOA1
REVEL	0.17	moderately benign-leaning
SaProt	LLR -5.25	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 0.65	GERP 2.2, phastCons 0.004
Regional constraint	o/e 1.01	unconstrained · MANE · 1,576 bp · p 0.87 · regional, not allelic
Overall
CADD	15.14	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.Phe95Leu
Coding: c.283T>C
MANE Select: NM_000039
dbSNP: rs2134231444
Type: single nucleotide variant
Location: chr11:116836329 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB
Residue 95: 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); an α-helix

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

Similar variants

APOA1 p.Phe95Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
APOA1 p.Arg197Pro Pathogenic ★★ same type
APOA1 p.Gln23Ter Pathogenic ★★ same type
APOA1 p.Gly50Arg Pathogenic ★★ same type
APOA1 c.-21+22G>A Uncertain significance ★★ same type
APOA1 p.Ala176Thr Uncertain significance ★★ ⚠ same type
APOA1 p.Ala176Val Uncertain significance ★★ ⚠ same type
APOA1 p.Ala204Val Uncertain significance ★★ ⚠ same type

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-phe95leu (accessed [today's date]).

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