Is APOB p.Pro554= (c.1662G>A) pathogenic?

APOB p.Pro554= (c.1662G>A) is classified Likely benign in APOB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-31). Ultra-rare (popmax 0.0333%, amr); Associated with familial hypobetalipoproteinemia 1.

What condition is associated with APOB p.Pro554= (c.1662G>A)?

APOB p.Pro554= (c.1662G>A) is associated with familial hypobetalipoproteinemia 1, familial hypercholesterolemia, hypercholesterolemia, autosomal dominant, type B (ClinVar).

How common is APOB p.Pro554= (c.1662G>A) in the general population?

APOB p.Pro554= (c.1662G>A) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

APOB p.Pro554=

c.1662G>A · rs149835778 · VCV942270

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Conditions

familial hypobetalipoproteinemia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.9	GERP -2.1
Overall
CADD	5.565	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Admixed American · 20/60,016 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00285% 46/1,613,818 alleles · ultra-rare exomes 31/1,461,538 · genomes 15/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,001
African / African-American	0.00267%	37,511
European (non-Finnish)	0.00186%	53,635
Remaining individualsnot grpmax-eligible	0.0016%	62,508
Finnishnot grpmax-eligible	0.00157%	63,750

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.Pro554=
Coding: c.1662G>A
MANE Select: NM_000384
dbSNP: rs149835778
Type: single nucleotide variant
Location: chr2:21028494 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 554: the vitellogenin domain; a UniProt-annotated variant site (in)

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: familial hypercholesterolemia hypercholesterolemia, autosomal dominant, type B

Similar variants

APOB p.Pro554Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
APOB p.Pro554Leu Conflicting classifications of pathogenicity ★ ⚠ 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
APOB p.Arg2085Ter Pathogenic/Likely 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-pro554 (accessed [today's date]).

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