Is APOC2 p.Lys41Thr (c.122A>C) pathogenic?

APOC2 p.Lys41Thr (c.122A>C) is classified Conflicting classifications of pathogenicity in APOC2 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2025-07-09). AlphaMissense: likely benign (0.154); Rare (popmax 0.148%, mid); Associated with APOC2-related disorder.

What condition is associated with APOC2 p.Lys41Thr (c.122A>C)?

APOC2 p.Lys41Thr (c.122A>C) is associated with APOC2-related disorder, familial apolipoprotein C-II deficiency (ClinVar).

How common is APOC2 p.Lys41Thr (c.122A>C) in the general population?

APOC2 p.Lys41Thr (c.122A>C) is rare (popmax 0.148%, mid) (gnomAD).

What do computational predictors say about APOC2 p.Lys41Thr (c.122A>C)?

AlphaMissense predicts likely benign (score 0.154) — an in-silico prediction, not a clinical call.

APOC2 p.Lys41Thr

c.122A>C · rs120074114 · VCV2581

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.154 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

APOC2-related disorder

Computational evidence

Protein change
AlphaMissense	0.154	likely benign
REVEL	0.471	indeterminate
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.5	GERP 0.75, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 767 bp · p 0.48 · regional, not allelic
Overall
CADD	17.25	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 0.148% Middle Eastern · 9/6,062 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.1%

Overall 0.086% 1,389/1,614,184 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	674
Ashkenazi Jewishnot grpmax-eligible	0.108%	925
European (non-Finnish)	0.107%	934
Remaining individualsnot grpmax-eligible	0.0704%	1,421
Admixed American	0.0367%	2,728
African / African-American	0.012%	8,339
South Asian	0.00988%	10,121
Finnishnot grpmax-eligible	0.00156%	64,034

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: APOC2
Protein: p.Lys41Thr
Coding: c.122A>C
MANE Select: NM_000483
dbSNP: rs120074114
Type: single nucleotide variant
Location: chr19:44948767 (GRCh38)
Gene constraint: LOEUF 1.054 · pLI 0.07 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 4 PDB
Residue 41: an α-helix; a UniProt-annotated variant site (in)

Full APOC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

APOC2-related disorder

Also linked: familial apolipoprotein C-II deficiency

Similar variants

APOC2 p.Gln92Ter Pathogenic/Likely pathogenic ★★ same condition
APOC2 p.Ala54Asp Uncertain significance ★★ ⚠ same condition
APOC2 p.Ala55Thr Uncertain significance ★★ ⚠ same condition
APOC2 p.Thr23Ile Uncertain significance ★★ ⚠ same condition
APOC2 p.Thr86Arg Uncertain significance ★★ ⚠ same condition
APOC2 c.56-4G>C Benign ★★ same condition
APOC2 p.Glu60Lys Benign/Likely benign ★★ same condition
APOC2 c.216-1G>A Pathogenic ★ 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/apoc2-p-lys41thr (accessed [today's date]).

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