Is APOOL p.Ala124Glu (c.371C>A) pathogenic?

APOOL p.Ala124Glu (c.371C>A) is classified Uncertain significance in APOOL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.8207); Very rare (popmax 0.000338%, nfe).

How common is APOOL p.Ala124Glu (c.371C>A) in the general population?

APOOL p.Ala124Glu (c.371C>A) is very rare (popmax 0.000338%, nfe) (gnomAD).

What do computational predictors say about APOOL p.Ala124Glu (c.371C>A)?

AlphaMissense predicts likely pathogenic (score 0.8207) — an in-silico prediction, not a clinical call.

APOOL p.Ala124Glu

c.371C>A · VCV4127956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000338%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8207	likely pathogenic · top 3% in APOOL
REVEL	0.309	indeterminate
SaProt	LLR -14.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.14	GERP -0.097, phastCons 0.006
Regional constraint	o/e 1.06	unconstrained · MANE · 84 kb · p 0.38 · regional, not allelic
Overall
CADD	17.29	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

Grpmax group 0.000338% European (non-Finnish) · 3/888,249 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000251% 3/1,195,072 alleles · very rare exomes 2/1,084,118 · genomes 1/110,954 · joint denominator

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: APOOL
Protein: p.Ala124Glu
Coding: c.371C>A
MANE Select: NM_198450
Type: single nucleotide variant
Location: chrX:85055902 (GRCh38)
Structure: AlphaFold pLDDT 70.83

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

Similar variants

APOOL p.Ala178Gly Uncertain significance ★ ⚠ same type
APOOL p.Ala241Ser Uncertain significance ★ ⚠ same type
APOOL p.Arg69Cys Uncertain significance ★ ⚠ same type
APOOL p.Arg69His Uncertain significance ★ ⚠ same type
APOOL p.Gln156His Uncertain significance ★ same type
APOOL p.Gln173His Uncertain significance ★ ⚠ same type
APOOL p.Glu30Lys Uncertain significance ★ ⚠ same type
APOOL p.Glu56Ala 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/apool-p-ala124glu (accessed [today's date]).

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