Is AFF4 p.Lys856Arg (c.2567A>G) pathogenic?

AFF4 p.Lys856Arg (c.2567A>G) is classified Likely benign in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: likely benign (0.0789); Ultra-rare (popmax 0.029%, eas); Associated with Inborn genetic diseases.

What condition is associated with AFF4 p.Lys856Arg (c.2567A>G)?

AFF4 p.Lys856Arg (c.2567A>G) is associated with Inborn genetic diseases (ClinVar).

How common is AFF4 p.Lys856Arg (c.2567A>G) in the general population?

AFF4 p.Lys856Arg (c.2567A>G) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about AFF4 p.Lys856Arg (c.2567A>G)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

AFF4 p.Lys856Arg

c.2567A>G · rs770762827 · VCV3092746

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -7.73	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 2	GERP 3.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,535 bp · p 0.44 · regional, not allelic
Overall
CADD	18.07	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 0.029% East Asian · 13/44,882 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00285% 46/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,452
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00246%	40,691
Admixed American	0.00167%	59,990

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: AFF4
Protein: p.Lys856Arg
Coding: c.2567A>G
MANE Select: NM_014423
dbSNP: rs770762827
Type: single nucleotide variant
Location: chr5:132892234 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 856: the 'disordered' region

Full AFF4 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

Similar variants

AFF4 p.Ala27Thr Uncertain significance ★★ ⚠ same condition
AFF4 p.Ala489Thr Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg153His Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg225His Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg3Cys Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg531Gln Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg711Thr Uncertain significance ★★ ⚠ same condition
AFF4 p.Asn762Ser 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/aff4-p-lys856arg (accessed [today's date]).

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