Is APOB p.Pro554Leu (c.1661C>T) pathogenic?

APOB p.Pro554Leu (c.1661C>T) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.109); Rare (popmax 0.841%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Pro554Leu (c.1661C>T)?

APOB p.Pro554Leu (c.1661C>T) is associated with Cardiovascular phenotype, familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is APOB p.Pro554Leu (c.1661C>T) in the general population?

APOB p.Pro554Leu (c.1661C>T) is rare (popmax 0.841%, afr) (gnomAD).

What do computational predictors say about APOB p.Pro554Leu (c.1661C>T)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

APOB p.Pro554Leu

c.1661C>T · rs12714214 · VCV199684

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.841%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.765	pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	26.2	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 0.841% African / African-American · 631/75,036 alleles

Filtering AF 0.787% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.765%

Overall 0.0497% 802/1,613,704 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.841%	119
Admixed American	0.0683%	1,463
Remaining individualsnot grpmax-eligible	0.048%	2,084
Middle Eastern	0.033%	3,030
East Asian	0.0156%	6,411
European (non-Finnish)	0.00746%	13,409
South Asian	0.0022%	45,539
Finnishnot grpmax-eligible	0.00157%	63,680

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.Pro554Leu
Coding: c.1661C>T
MANE Select: NM_000384
dbSNP: rs12714214
Type: single nucleotide variant
Location: chr2:21028495 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia hypercholesterolemia, familial, 1 hypercholesterolemia, autosomal dominant, type B familial hypobetalipoproteinemia 1

Similar variants

APOB p.Pro554= Likely benign ★★ same residue
APOB p.Pro554Arg 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-pro554leu (accessed [today's date]).

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