Is APBA3 p.Arg252Cys (c.754C>T) pathogenic?

APBA3 p.Arg252Cys (c.754C>T) is classified Uncertain significance in APBA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-28). AlphaMissense: likely benign (0.289); Ultra-rare (popmax 0.0441%, eas).

How common is APBA3 p.Arg252Cys (c.754C>T) in the general population?

APBA3 p.Arg252Cys (c.754C>T) is ultra-rare (popmax 0.0441%, eas) (gnomAD).

What do computational predictors say about APBA3 p.Arg252Cys (c.754C>T)?

AlphaMissense predicts likely benign (score 0.289) — an in-silico prediction, not a clinical call.

APBA3 p.Arg252Cys

c.754C>T · rs764194208 · VCV2516478

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.289 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0441%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.289	likely benign
REVEL	0.465	indeterminate
SaProt	LLR -12.33	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.71, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 9,235 bp · p 0.12 · regional, not allelic
Overall
CADD	26.3	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 0.0441% East Asian · 18/40,776 alleles

Filtering AF 0.0285% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0235%

Overall 0.0061% 94/1,540,174 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0441%	2,265
Middle Eastern	0.0191%	5,248
South Asian	0.0107%	9,304
Remaining individualsnot grpmax-eligible	0.0101%	9,905
European (non-Finnish)	0.00517%	19,358
Admixed American	0.00206%	48,546

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: APBA3
Protein: p.Arg252Cys
Coding: c.754C>T
MANE Select: NM_004886
dbSNP: rs764194208
Type: single nucleotide variant
Location: chr19:3754203 (GRCh38)
Gene constraint: LOEUF 1.237 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.79 · 3 PDB
Residue 252: the pid domain; the 'required for interaction with necab3' region

Full APBA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBA3 p.Arg252His Uncertain significance ★ ⚠ same residue
APBA3 p.Ala158Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala202Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala223Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala308Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala317Val Uncertain significance ★ ⚠ same type
APBA3 p.Ala335Thr Uncertain significance ★ ⚠ same type
APBA3 p.Ala335Val 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/apba3-p-arg252cys (accessed [today's date]).

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