Is APOB p.Val593Leu (c.1777G>C) pathogenic?

APOB p.Val593Leu (c.1777G>C) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: ambiguous (0.445); Rare (popmax 0.103%, sas); Associated with hypercholesterolemia, autosomal dominant, type B.

How common is APOB p.Val593Leu (c.1777G>C) in the general population?

APOB p.Val593Leu (c.1777G>C) is rare (popmax 0.103%, sas) (gnomAD).

What do computational predictors say about APOB p.Val593Leu (c.1777G>C)?

AlphaMissense predicts ambiguous (score 0.445) — an in-silico prediction, not a clinical call.

APOB p.Val593Leu

Q: What condition is associated with APOB p.Val593Leu (c.1777G>C)?

APOB p.Val593Leu (c.1777G>C) is associated with hypercholesterolemia, autosomal dominant, type B, familial hypobetalipoproteinemia 1 (ClinVar).

c.1777G>C · rs781228974 · VCV630349

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.445 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, sas)

Conditions

hypercholesterolemia, autosomal dominant, type B

Computational evidence

Protein change
AlphaMissense	0.445	ambiguous
REVEL	0.306	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	23.5	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 0.103% South Asian · 94/91,088 alleles

Filtering AF 0.0863% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.08%

Overall 0.00607% 98/1,614,058 alleles · rare exomes 95/1,461,880 · genomes 3/152,178 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.103%	969
Remaining individualsnot grpmax-eligible	0.0064%	15,622

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.Val593Leu
Coding: c.1777G>C
MANE Select: NM_000384
dbSNP: rs781228974
Type: single nucleotide variant
Location: chr2:21028379 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 593: 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 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
APOB p.Arg2520Ter 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-val593leu (accessed [today's date]).

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