Is APOB p.Ser986Pro (c.2956T>C) pathogenic?

APOB p.Ser986Pro (c.2956T>C) is classified Uncertain significance in APOB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-14). AlphaMissense: likely benign (0.1706); Very rare (popmax 0.000169%, nfe); Associated with familial hypercholesterolemia.

What condition is associated with APOB p.Ser986Pro (c.2956T>C)?

APOB p.Ser986Pro (c.2956T>C) is associated with familial hypercholesterolemia (ClinVar).

How common is APOB p.Ser986Pro (c.2956T>C) in the general population?

APOB p.Ser986Pro (c.2956T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about APOB p.Ser986Pro (c.2956T>C)?

AlphaMissense predicts likely benign (score 0.1706) — an in-silico prediction, not a clinical call.

APOB p.Ser986Pro

c.2956T>C · VCV4852794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.1706	likely benign
REVEL	0.258	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	23.6	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,024 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,152 alleles · very rare exomes 2/1,461,874 · genomes 0/152,278 · joint denominator

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.Ser986Pro
Coding: c.2956T>C
MANE Select: NM_000384
Type: single nucleotide variant
Location: chr2:21019766 (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

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

Similar variants

APOB p.Ser986= Likely benign ★ same residue
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

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-ser986pro (accessed [today's date]).

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