Is APBA2 p.Ile516Phe (c.1546A>T) pathogenic?

APBA2 p.Ile516Phe (c.1546A>T) is classified Uncertain significance in APBA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely pathogenic (0.9911); Absent from gnomAD v4.1.

How common is APBA2 p.Ile516Phe (c.1546A>T) in the general population?

APBA2 p.Ile516Phe (c.1546A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APBA2 p.Ile516Phe (c.1546A>T)?

AlphaMissense predicts likely pathogenic (score 0.9911) — an in-silico prediction, not a clinical call.

APBA2 p.Ile516Phe

c.1546A>T · VCV3924378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9911 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9911	likely pathogenic
REVEL	0.589	indeterminate
SaProt	LLR -14.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.42	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Overall
CADD	32.0	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: APBA2
Protein: p.Ile516Phe
Coding: c.1546A>T
MANE Select: NM_001353788
Type: single nucleotide variant
Location: chr15:29105400 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 59.74
Residue 516: the pid domain

Full APBA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBA2 p.Val77Met Uncertain significance ★★ ⚠ same type
APBA2 c.1216-9T>C Benign ★★ same type
APBA2 c.1525-8C>G Likely benign ★★ same type
APBA2 c.1705-9C>T Benign ★★ same type
APBA2 p.Asp87= Benign ★★ same type
APBA2 p.Gly206= Benign ★★ same type
APBA2 p.His127= Benign ★★ same type
APBA2 p.Ile101= Benign ★★ 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/apba2-p-ile516phe (accessed [today's date]).

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