Is APOB p.Pro646= (c.1938A>G) pathogenic?

APOB p.Pro646= (c.1938A>G) is classified Likely benign in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-11). Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with APOB p.Pro646= (c.1938A>G)?

APOB p.Pro646= (c.1938A>G) is associated with Cardiovascular phenotype (ClinVar).

How common is APOB p.Pro646= (c.1938A>G) in the general population?

APOB p.Pro646= (c.1938A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

APOB p.Pro646=

c.1938A>G · VCV4613657

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.99	GERP -3.8
Overall
CADD	6.191	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,076 alleles

Overall 0.000124% 2/1,613,982 alleles · very rare exomes 2/1,461,662 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,498
South Asiangrpmax	0.0011%	91,076

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.Pro646=
Coding: c.1938A>G
MANE Select: NM_000384
Type: single nucleotide variant
Location: chr2:21027957 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 646: the vitellogenin domain

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-pro646 (accessed [today's date]).

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