Is APBA1 p.Ser566Cys (c.1697C>G) pathogenic?

APBA1 p.Ser566Cys (c.1697C>G) is classified Uncertain significance in APBA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely benign (0.1006); Ultra-rare (popmax 0.0351%, sas).

How common is APBA1 p.Ser566Cys (c.1697C>G) in the general population?

APBA1 p.Ser566Cys (c.1697C>G) is ultra-rare (popmax 0.0351%, sas) (gnomAD).

What do computational predictors say about APBA1 p.Ser566Cys (c.1697C>G)?

AlphaMissense predicts likely benign (score 0.1006) — an in-silico prediction, not a clinical call.

APBA1 p.Ser566Cys

c.1697C>G · VCV3924120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1006 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1006	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 807 bp · p 0.25 · regional, not allelic
Overall
CADD	26.9	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 0.0351% South Asian · 32/91,080 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00198% 32/1,614,146 alleles · ultra-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: APBA1
Protein: p.Ser566Cys
Coding: c.1697C>G
MANE Select: NM_001163
Type: single nucleotide variant
Location: chr9:69456338 (GRCh38)
Gene constraint: LOEUF 0.978 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.85 · 8 PDB
Residue 566: the pid domain

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-ser566cys (accessed [today's date]).

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