Is APOB p.Phe661= (c.1983T>C) pathogenic?

APOB p.Phe661= (c.1983T>C) is classified Likely benign in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-08). Ultra-rare (popmax 0.0165%, mid); Associated with hypercholesterolemia, autosomal dominant, type B.

What condition is associated with APOB p.Phe661= (c.1983T>C)?

APOB p.Phe661= (c.1983T>C) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

How common is APOB p.Phe661= (c.1983T>C) in the general population?

APOB p.Phe661= (c.1983T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

APOB p.Phe661=

c.1983T>C · rs2465419965 · VCV2923092

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

hypercholesterolemia, autosomal dominant, type B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.85	GERP -3.1, phastCons 0.97
Overall
CADD	11.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.19e-05% 1/1,614,226 alleles · ultra-rare exomes 1/1,461,876 · genomes 0/152,350 · 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: APOB
Protein: p.Phe661=
Coding: c.1983T>C
MANE Select: NM_000384
dbSNP: rs2465419965
Type: single nucleotide variant
Location: chr2:21027912 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 661: the vitellogenin domain

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

Disease context

hypercholesterolemia, autosomal dominant, type B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypobetalipoproteinemia 1

Similar variants

APOB p.Phe661Val Uncertain significance ★ ⚠ 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
APOB p.Arg2513Ter 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-phe661 (accessed [today's date]).

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