Is APOA4 p.Leu66Val (c.196C>G) pathogenic?

APOA4 p.Leu66Val (c.196C>G) is classified Pathogenic in APOA4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-02-26). AlphaMissense: likely benign (0.0845); Very rare (popmax 0.000254%, nfe); Associated with tubulointerstitial kidney disease, autosomal dominant 6.

What condition is associated with APOA4 p.Leu66Val (c.196C>G)?

APOA4 p.Leu66Val (c.196C>G) is associated with tubulointerstitial kidney disease, autosomal dominant 6 (ClinVar).

How common is APOA4 p.Leu66Val (c.196C>G) in the general population?

APOA4 p.Leu66Val (c.196C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about APOA4 p.Leu66Val (c.196C>G)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

APOA4 p.Leu66Val

c.196C>G · VCV3764740

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tubulointerstitial kidney disease, autosomal dominant 6

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign ⚠ discordant with ClinVar
REVEL	0.268	benign-leaning
SaProt	LLR -7.14	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 1.1	GERP 0.2, phastCons 0.12
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	8.787	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 0.000254% European (non-Finnish) · 3/1,180,028 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,606 alleles · very rare

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: APOA4
Protein: p.Leu66Val
Coding: c.196C>G
MANE Select: NM_000482
Type: single nucleotide variant
Location: chr11:116821862 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 2 PDB
Residue 66: the '13 x 22 aa approximate tandem repeats' region; a UniProt-annotated variant site (in adtkd6; likely pathogenic)

Full APOA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tubulointerstitial kidney disease, autosomal dominant 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APOA4 p.Asp33Asn Pathogenic ⚠ same condition
APOA4 p.Ala172Thr Uncertain significance ★★ ⚠ same type
APOA4 p.Ala333Val Uncertain significance ★★ ⚠ same type
APOA4 p.Ala60Asp Uncertain significance ★★ ⚠ same type
APOA4 p.Arg166Ser Uncertain significance ★★ ⚠ same type
APOA4 p.Arg275Cys Uncertain significance ★★ ⚠ same type
APOA4 p.Gln50Arg Uncertain significance ★★ ⚠ same type
APOA4 p.Gln50Lys Uncertain significance ★★ ⚠ same type

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/apoa4-p-leu66val (accessed [today's date]).

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