Is APBB1 p.Gln694His (c.2082G>T) pathogenic?

APBB1 p.Gln694His (c.2082G>T) is classified Uncertain significance in APBB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: ambiguous (0.4908); Very rare (popmax 0.00711%, amr).

How common is APBB1 p.Gln694His (c.2082G>T) in the general population?

APBB1 p.Gln694His (c.2082G>T) is very rare (popmax 0.00711%, amr) (gnomAD).

What do computational predictors say about APBB1 p.Gln694His (c.2082G>T)?

AlphaMissense predicts ambiguous (score 0.4908) — an in-silico prediction, not a clinical call.

APBB1 p.Gln694His

c.2082G>T · rs767793385 · VCV3127669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00711%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4908	ambiguous
REVEL	0.139	moderately benign-leaning
SaProt	LLR -6.99	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.62, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 336 bp · p 0.064 · regional, not allelic
Overall
CADD	25.0	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 0.00711% Admixed American · 4/56,262 alleles

Filtering AF 0.00236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0017% 27/1,585,170 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00711%	14,066
European (non-Finnish)	0.00189%	52,907
Remaining individualsnot grpmax-eligible	0.00164%	60,984

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.Gln694His
Coding: c.2082G>T
MANE Select: NM_001164
dbSNP: rs767793385
Type: single nucleotide variant
Location: chr11:6395585 (GRCh38)
Gene constraint: LOEUF 0.401 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 60.75 · 11 PDB
Residue 694: the pid 2 domain

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

Similar variants

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
APBB1 p.Ala157Val 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-gln694his (accessed [today's date]).

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