Is AFF3 p.His889Gln (c.2667C>G) pathogenic?

AFF3 p.His889Gln (c.2667C>G) is classified Uncertain significance in AFF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-07). AlphaMissense: likely benign (0.1549); Very rare (popmax 0.00167%, amr); Associated with AFF3-related disorder.

What condition is associated with AFF3 p.His889Gln (c.2667C>G)?

AFF3 p.His889Gln (c.2667C>G) is associated with AFF3-related disorder (ClinVar).

How common is AFF3 p.His889Gln (c.2667C>G) in the general population?

AFF3 p.His889Gln (c.2667C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about AFF3 p.His889Gln (c.2667C>G)?

AlphaMissense predicts likely benign (score 0.1549) — an in-silico prediction, not a clinical call.

AFF3 p.His889Gln

c.2667C>G · rs117712488 · VCV2630555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1549 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AFF3-related disorder

Computational evidence

Protein change
AlphaMissense	0.1549	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Pangolin	Δ0.38	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.2	GERP 2.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.083 · regional, not allelic
Overall
CADD	23.7	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 0.00167% Admixed American · 1/60,016 alleles

Overall 6.84e-05% 1/1,461,854 alleles · very 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: AFF3
Protein: p.His889Gln
Coding: c.2667C>G
MANE Select: NM_001386135
dbSNP: rs117712488
Type: single nucleotide variant
Location: chr2:99582924 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 889: the 'disordered' region

Full AFF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AFF3-related disorder

Similar variants

AFF3 p.Met238Arg Likely pathogenic ★ ⚠ same condition
AFF3 p.His211Asn Uncertain significance ★ ⚠ same condition
AFF3 p.Lys271Thr Uncertain significance ★ ⚠ same condition
AFF3 p.Pro332Thr Uncertain significance ★ ⚠ same condition
AFF3 p.Ala203Ser Uncertain significance ⚠ same condition
AFF3 c.2591+5G>A Benign same condition
AFF3 c.922-10C>T Benign same condition
AFF3 p.Arg390= Likely benign same condition

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/aff3-p-his889gln (accessed [today's date]).

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