Is APOA5 p.Leu136Pro (c.407T>C) pathogenic?

APOA5 p.Leu136Pro (c.407T>C) is classified Uncertain significance in APOA5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-19). AlphaMissense: likely pathogenic (0.8918); Absent from gnomAD v4.1.

How common is APOA5 p.Leu136Pro (c.407T>C) in the general population?

APOA5 p.Leu136Pro (c.407T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOA5 p.Leu136Pro (c.407T>C)?

AlphaMissense predicts likely pathogenic (score 0.8918) — an in-silico prediction, not a clinical call.

APOA5 p.Leu136Pro

c.407T>C · rs2134203531 · VCV1677337

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8918 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8918	likely pathogenic · top 1% in APOA5
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -12.16	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 3.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,729 bp · p 0.086 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: APOA5
Protein: p.Leu136Pro
Coding: c.407T>C
MANE Select: NM_001371904
dbSNP: rs2134203531
Type: single nucleotide variant
Location: chr11:116790822 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.38

Full APOA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOA5 p.Gln97Ter Pathogenic ★★ same type
APOA5 c.161+3G>A Uncertain significance ★★ same type
APOA5 c.161+5G>C Uncertain significance ★★ same type
APOA5 p.Ala105Ser Uncertain significance ★★ ⚠ same type
APOA5 p.Ala244Ser Uncertain significance ★★ ⚠ same type
APOA5 p.Ala302Val Uncertain significance ★★ ⚠ same type
APOA5 p.Ala82Val Uncertain significance ★★ ⚠ same type
APOA5 p.Arg143His 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/apoa5-p-leu136pro (accessed [today's date]).

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