Is AFF3 p.Arg947Gln (c.2840G>A) pathogenic?

AFF3 p.Arg947Gln (c.2840G>A) is classified Conflicting classifications of pathogenicity in AFF3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-11). AlphaMissense: likely benign (0.0689); Very rare (popmax 0.00337%, amr); Associated with Inborn genetic diseases.

What condition is associated with AFF3 p.Arg947Gln (c.2840G>A)?

AFF3 p.Arg947Gln (c.2840G>A) is associated with Inborn genetic diseases, KINSSHIP syndrome (ClinVar).

How common is AFF3 p.Arg947Gln (c.2840G>A) in the general population?

AFF3 p.Arg947Gln (c.2840G>A) is very rare (popmax 0.00337%, amr) (gnomAD).

What do computational predictors say about AFF3 p.Arg947Gln (c.2840G>A)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

AFF3 p.Arg947Gln

c.2840G>A · VCV3600986

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00337%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -5.11	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 5.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.083 · regional, not allelic
Overall
CADD	19.0	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 0.00337% Admixed American · 2/59,396 alleles

Filtering AF 0.000559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000931% 15/1,611,226 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00337%	29,698
Finnishnot grpmax-eligible	0.00156%	64,024
European (non-Finnish)	0.00102%	98,247

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.Arg947Gln
Coding: c.2840G>A
MANE Select: NM_001386135
Type: single nucleotide variant
Location: chr2:99578405 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 947: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: KINSSHIP syndrome

Similar variants

AFF3 p.Arg947Gly Uncertain significance ★ ⚠ same residue
AFF3 p.Ala233Thr Pathogenic ★★ ⚠ same condition
AFF3 p.Ala233Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF3 p.Ile1147Asn Uncertain significance ★★ ⚠ same condition
AFF3 p.Leu370Phe Uncertain significance ★★ ⚠ same condition
AFF3 p.Pro321Leu Uncertain significance ★★ ⚠ same condition
AFF3 p.Ser222Thr Uncertain significance ★★ ⚠ same condition
AFF3 p.Thr950Met Uncertain significance ★★ ⚠ 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-arg947gln (accessed [today's date]).

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