Is APOB p.Ala3175Pro (c.9523G>C) pathogenic?

APOB p.Ala3175Pro (c.9523G>C) is classified Likely benign in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-02). AlphaMissense: likely pathogenic (0.7415); Very rare (popmax 0.000847%, nfe); Associated with familial hypobetalipoproteinemia 1.

What condition is associated with APOB p.Ala3175Pro (c.9523G>C)?

APOB p.Ala3175Pro (c.9523G>C) is associated with familial hypobetalipoproteinemia 1, hypercholesterolemia, autosomal dominant, type B (ClinVar).

How common is APOB p.Ala3175Pro (c.9523G>C) in the general population?

APOB p.Ala3175Pro (c.9523G>C) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about APOB p.Ala3175Pro (c.9523G>C)?

AlphaMissense predicts likely pathogenic (score 0.7415) — an in-silico prediction, not a clinical call.

APOB p.Ala3175Pro

c.9523G>C · rs200584734 · VCV2179838

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7415 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial hypobetalipoproteinemia 1

Computational evidence

Protein change
AlphaMissense	0.7415	likely pathogenic · top 4% in APOB
REVEL	0.262	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -2.4, phastCons 0.084
Regional constraint	o/e 1.03	unconstrained · MANE · 9,629 bp · p 0.051 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,179,950 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,613,958 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: APOB
Protein: p.Ala3175Pro
Coding: c.9523G>C
MANE Select: NM_000384
dbSNP: rs200584734
Type: single nucleotide variant
Location: chr2:21007345 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 3175: the 'heparin-binding' region; the 'basic (possible receptor binding region)' region

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

Disease context

familial hypobetalipoproteinemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, autosomal dominant, type B

Similar variants

APOB p.Ala3175fs Pathogenic ★ same residue
APOB p.Ala3175Ser Uncertain significance ★★ ⚠ same residue
APOB p.Ala3175= Likely benign ★ same residue
APOB c.1830-1G>A Pathogenic ★★ same condition
APOB c.2604+1G>A Likely pathogenic ★★ same condition
APOB c.537+1G>T Pathogenic/Likely pathogenic ★★ same condition
APOB p.Arg1333Ter Pathogenic ★★ same condition
APOB p.Arg2012Ter Pathogenic ★★ 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/apob-p-ala3175pro (accessed [today's date]).

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