Is APOB p.Trp1237Arg (c.3709T>C) pathogenic?

APOB p.Trp1237Arg (c.3709T>C) is classified Uncertain significance in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.5921); Very rare (popmax 0.004%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Trp1237Arg (c.3709T>C)?

APOB p.Trp1237Arg (c.3709T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is APOB p.Trp1237Arg (c.3709T>C) in the general population?

APOB p.Trp1237Arg (c.3709T>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about APOB p.Trp1237Arg (c.3709T>C)?

AlphaMissense predicts likely pathogenic (score 0.5921) — an in-silico prediction, not a clinical call.

APOB p.Trp1237Arg

c.3709T>C · VCV4124771

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5921	likely pathogenic · top 8% in APOB
REVEL	0.392	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	23.9	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 0.004% African / African-American · 3/74,932 alleles

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

Overall 0.000372% 6/1,613,994 alleles · very rare exomes 4/1,461,786 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,977
South Asian	0.0022%	45,541
European (non-Finnish)	8.47e-05%	1,179,979

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.Trp1237Arg
Coding: c.3709T>C
MANE Select: NM_000384
Type: single nucleotide variant
Location: chr2:21014581 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)

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.Trp1237Gly Conflicting classifications of pathogenicity ★ same residue
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

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-trp1237arg (accessed [today's date]).

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