Is APOM p.Glu59Lys (c.175G>A) pathogenic?

APOM p.Glu59Lys (c.175G>A) is classified Uncertain significance in APOM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: ambiguous (0.439); Very rare (popmax 0.000169%, nfe).

How common is APOM p.Glu59Lys (c.175G>A) in the general population?

APOM p.Glu59Lys (c.175G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about APOM p.Glu59Lys (c.175G>A)?

AlphaMissense predicts ambiguous (score 0.439) — an in-silico prediction, not a clinical call.

APOM p.Glu59Lys

c.175G>A · VCV3886867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.439 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.439	ambiguous
REVEL	0.054	moderately benign-leaning
SaProt	LLR -4.92	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 8.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,119 bp · p 0.03 · regional, not allelic
Overall
CADD	23.2	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) · 2/1,180,024 alleles

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

Overall 0.000137% 2/1,461,870 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: APOM
Protein: p.Glu59Lys
Coding: c.175G>A
MANE Select: NM_019101
Type: single nucleotide variant
Location: chr6:31656532 (GRCh38)
Gene constraint: LOEUF 1.437 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.61 · 3 PDB
Residue 59: an α-helix; a disulfide bond

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

Similar variants

APOM p.Arg89Pro Uncertain significance ★ ⚠ same type
APOM p.Asn135Ile Uncertain significance ★ ⚠ same type
APOM p.Gly140Arg Uncertain significance ★ ⚠ same type
APOM p.Leu104Pro Uncertain significance ★ ⚠ same type
APOM p.Met80Ile Uncertain significance ★ ⚠ same type
APOM p.Pro24Thr Uncertain significance ★ ⚠ same type
APOM p.Pro79Leu Uncertain significance ★ ⚠ same type
APOM p.Tyr141Asn 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/apom-p-glu59lys (accessed [today's date]).

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