Is APOA5 p.Ser19Trp (c.56C>G) pathogenic?

APOA5 p.Ser19Trp (c.56C>G) is classified Benign/Likely benign in APOA5 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1745); Common (popmax 13.8%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with APOA5 p.Ser19Trp (c.56C>G)?

APOA5 p.Ser19Trp (c.56C>G) is associated with Cardiovascular phenotype, hyperlipoproteinemia type V, hypertriglyceridemia 1 (ClinVar).

What do computational predictors say about APOA5 p.Ser19Trp (c.56C>G)?

AlphaMissense predicts likely benign (score 0.1745) — an in-silico prediction, not a clinical call.

APOA5 p.Ser19Trp

Q: How common is APOA5 p.Ser19Trp (c.56C>G) in the general population?

APOA5 p.Ser19Trp (c.56C>G) is common (popmax 13.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.56C>G · rs3135506 · VCV4403

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1745 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 13.8%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1745	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -9.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 3.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,729 bp · p 0.086 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.8% Admixed American · 8,150/59,000 alleles

Filtering AF 13.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.5%

Overall 6.24% 100,249/1,607,778 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	13.8%	7
Amishnot grpmax-eligible	12%	8
Ashkenazi Jewishnot grpmax-eligible	6.54%	15
African / African-American	6.31%	16
European (non-Finnish)	6.27%	16
Finnishnot grpmax-eligible	6.14%	16
Remaining individualsnot grpmax-eligible	6.12%	16
Middle Eastern	5.5%	18
South Asian	3.88%	26
East Asian	0.0494%	2,025

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: APOA5
Protein: p.Ser19Trp
Coding: c.56C>G
MANE Select: NM_001371904
dbSNP: rs3135506
Type: single nucleotide variant
Location: chr11:116791691 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.38
Residue 19: a UniProt-annotated variant site (in allele apoa5*3; correlated with high plasma triglyceride levels)

Full APOA5 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

Also linked: hyperlipoproteinemia type V hypertriglyceridemia 1

Similar variants

APOA5 p.Ser19Leu Uncertain significance ★★ ⚠ same residue
APOA5 p.Ser19= Likely benign ★ same residue
APOA5 p.Gln97Ter Pathogenic ★★ same condition
APOA5 c.161+3G>A Uncertain significance ★★ same condition
APOA5 c.161+5G>C Uncertain significance ★★ same condition
APOA5 p.Ala244Ser Uncertain significance ★★ ⚠ same condition
APOA5 p.Ala302Val Uncertain significance ★★ ⚠ same condition
APOA5 p.Ala82Val 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/apoa5-p-ser19trp (accessed [today's date]).

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