Is APOE p.Ser314Arg (c.940A>C) pathogenic?

APOE p.Ser314Arg (c.940A>C) is classified Conflicting classifications of pathogenicity in APOE (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-11). AlphaMissense: likely benign (0.192); Ultra-rare (popmax 0.0308%, sas); Associated with Cardiovascular phenotype.

What condition is associated with APOE p.Ser314Arg (c.940A>C)?

APOE p.Ser314Arg (c.940A>C) is associated with Cardiovascular phenotype, sea-blue histiocyte syndrome, hyperlipoproteinemia type 3 (ClinVar).

How common is APOE p.Ser314Arg (c.940A>C) in the general population?

APOE p.Ser314Arg (c.940A>C) is ultra-rare (popmax 0.0308%, sas) (gnomAD).

What do computational predictors say about APOE p.Ser314Arg (c.940A>C)?

AlphaMissense predicts likely benign (score 0.192) — an in-silico prediction, not a clinical call.

APOE p.Ser314Arg

c.940A>C · rs28931579 · VCV17876

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.192 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0308%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.192	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.1	GERP -3.2
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	11.65	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 0.0308% South Asian · 28/90,878 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00557% 89/1,596,790 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0308%	3,246
Remaining individualsnot grpmax-eligible	0.00483%	20,711
European (non-Finnish)	0.00466%	21,441
East Asian	0.00223%	44,838
Admixed American	0.00167%	59,906
African / African-American	0.00133%	74,964

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: APOE
Protein: p.Ser314Arg
Coding: c.940A>C
MANE Select: NM_000041
dbSNP: rs28931579
Type: single nucleotide variant
Location: chr19:44909236 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 314: the 'homooligomerization' region; a UniProt-annotated variant site (in hlpp3; apoe3 washington); a UniProt-annotated variant site (in apoe4 hg)

Full APOE 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: sea-blue histiocyte syndrome hyperlipoproteinemia type 3

Similar variants

APOE p.Ser314= Likely benign ★★ same residue
APOE p.Arg154Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOE p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
APOE p.Trp228Ter Likely pathogenic ★★ same condition
APOE p.Arg246Pro Uncertain significance ★★ same condition
APOE p.Arg269Gly Uncertain significance ★★ ⚠ same condition
APOE p.Arg56His Uncertain significance ★★ ⚠ same condition
APOE p.Gln119Pro 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/apoe-p-ser314arg (accessed [today's date]).

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