Is APOB p.Arg253Ser (c.759G>T) pathogenic?

APOB p.Arg253Ser (c.759G>T) is classified Likely benign in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-31). AlphaMissense: ambiguous (0.3974); Very rare (popmax 0.000424%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Arg253Ser (c.759G>T)?

APOB p.Arg253Ser (c.759G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is APOB p.Arg253Ser (c.759G>T) in the general population?

APOB p.Arg253Ser (c.759G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about APOB p.Arg253Ser (c.759G>T)?

AlphaMissense predicts ambiguous (score 0.3974) — an in-silico prediction, not a clinical call.

APOB p.Arg253Ser

c.759G>T · rs2465441585 · VCV1759705

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3974	ambiguous
REVEL	0.048	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.31	GERP -0.034
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	17.05	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 0.000424% European (non-Finnish) · 5/1,180,036 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,134 alleles · very rare exomes 6/1,461,812 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.000424%	236,007

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg253Ser
Coding: c.759G>T
MANE Select: NM_000384
dbSNP: rs2465441585
Type: single nucleotide variant
Location: chr2:21035643 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 253: the vitellogenin domain; the 'heparin-binding' region

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

Similar variants

APOB p.Arg490Trp Pathogenic/Likely pathogenic ★★ same condition
APOB c.1124+3A>G Uncertain significance ★★ same condition
APOB c.11788+4A>G Uncertain significance ★★ same condition
APOB c.12087+2T>C Uncertain significance ★★ same condition
APOB p.Ala1320Thr Uncertain significance ★★ ⚠ same condition
APOB p.Ala1695Val Uncertain significance ★★ ⚠ same condition
APOB p.Ala1975Ser Uncertain significance ★★ ⚠ same condition
APOB p.Ala3008Thr 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-arg253ser (accessed [today's date]).

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