Is APBA1 p.Ile726Val (c.2176A>G) pathogenic?

APBA1 p.Ile726Val (c.2176A>G) is classified Uncertain significance in APBA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely benign (0.169); Ultra-rare (popmax 0.0117%, amr).

How common is APBA1 p.Ile726Val (c.2176A>G) in the general population?

APBA1 p.Ile726Val (c.2176A>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about APBA1 p.Ile726Val (c.2176A>G)?

AlphaMissense predicts likely benign (score 0.169) — an in-silico prediction, not a clinical call.

APBA1 p.Ile726Val

c.2176A>G · VCV3924140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.169 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.169	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -9.41	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 18 kb · p 0.61 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0117% Admixed American · 7/60,014 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000958% 14/1,461,320 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,573
South Asian	0.00769%	13,006

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: APBA1
Protein: p.Ile726Val
Coding: c.2176A>G
MANE Select: NM_001163
Type: single nucleotide variant
Location: chr9:69449589 (GRCh38)
Gene constraint: LOEUF 0.978 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.85 · 8 PDB
Residue 726: the pdz 1 domain; an α-helix

Full APBA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBA1 p.Asn810Ser Uncertain significance ★★ ⚠ same type
APBA1 p.Ala225Val Uncertain significance ★ ⚠ same type
APBA1 p.Ala329Val Uncertain significance ★ ⚠ same type
APBA1 p.Ala345Thr Uncertain significance ★ ⚠ same type
APBA1 p.Ala506Pro Uncertain significance ★ ⚠ same type
APBA1 p.Ala574Val Uncertain significance ★ ⚠ same type
APBA1 p.Arg143Cys Uncertain significance ★ ⚠ same type
APBA1 p.Arg177His 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/apba1-p-ile726val (accessed [today's date]).

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