Is APOB p.Glu605Lys (c.1813G>A) pathogenic?

APOB p.Glu605Lys (c.1813G>A) is classified Uncertain significance in APOB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-29). AlphaMissense: likely benign (0.157); Very rare (popmax 0.00401%, afr); Associated with familial hypercholesterolemia.

What condition is associated with APOB p.Glu605Lys (c.1813G>A)?

APOB p.Glu605Lys (c.1813G>A) is associated with familial hypercholesterolemia (ClinVar).

How common is APOB p.Glu605Lys (c.1813G>A) in the general population?

APOB p.Glu605Lys (c.1813G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about APOB p.Glu605Lys (c.1813G>A)?

AlphaMissense predicts likely benign (score 0.157) — an in-silico prediction, not a clinical call.

APOB p.Glu605Lys

c.1813G>A · VCV4057071

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.157 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.157	likely benign
REVEL	0.275	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,896 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,613,390 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,965
European (non-Finnish)	8.48e-05%	1,179,434

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.Glu605Lys
Coding: c.1813G>A
MANE Select: NM_000384
Type: single nucleotide variant
Location: chr2:21028343 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 605: the vitellogenin domain

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

Disease context

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

Similar variants

APOB p.Arg2085Ter Pathogenic/Likely pathogenic ★★ same condition
APOB p.Arg3527Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOB p.Arg3527Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOB p.Ala1695Val Uncertain significance ★★ ⚠ same condition
APOB p.Ala68Thr Uncertain significance ★★ ⚠ same condition
APOB p.Arg3183Gly Uncertain significance ★★ ⚠ same condition
APOB p.Arg3311Ile Uncertain significance ★★ ⚠ same condition
APOB p.Asn3358His Uncertain significance ★★ 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-glu605lys (accessed [today's date]).

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