Is APBB1 p.Ala194Asp (c.581C>A) pathogenic?

APBB1 p.Ala194Asp (c.581C>A) is classified Uncertain significance in APBB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.0954); Ultra-rare (popmax 0.0158%, sas).

How common is APBB1 p.Ala194Asp (c.581C>A) in the general population?

APBB1 p.Ala194Asp (c.581C>A) is ultra-rare (popmax 0.0158%, sas) (gnomAD).

What do computational predictors say about APBB1 p.Ala194Asp (c.581C>A)?

AlphaMissense predicts likely benign (score 0.0954) — an in-silico prediction, not a clinical call.

APBB1 p.Ala194Asp

c.581C>A · VCV3924644

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0954 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0954	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.29	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 5.7	GERP -0.59, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 15 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	18.39	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 0.0158% South Asian · 14/88,606 alleles

Filtering AF 0.00954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00764%

Overall 0.00111% 16/1,447,264 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0158%	6,329
Remaining individualsnot grpmax-eligible	0.00162%	61,840
European (non-Finnish)	8.53e-05%	1,171,654

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: APBB1
Protein: p.Ala194Asp
Coding: c.581C>A
MANE Select: NM_001164
Type: single nucleotide variant
Location: chr11:6410767 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.75 · 11 PDB
Residue 194: the 'disordered' region

Full APBB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APBB1 p.Ala194Val Uncertain significance ★ ⚠ same residue
SMPD1 p.Arg498Leu Pathogenic ★★ same type
APBB1 p.Ala371= Benign ★★ same type
APBB1 p.Arg51Cys Benign ★★ ⚠ same type
APBB1 p.Asn126= Benign ★★ same type
APBB1 p.Leu385= Benign ★★ same type
APBB1 p.Met327Val Likely benign ★★ same type
APBB1 c.721+1G>T 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/apbb1-p-ala194asp (accessed [today's date]).

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