Is AFF2 p.His820Arg (c.2459A>G) pathogenic?

AFF2 p.His820Arg (c.2459A>G) is classified Uncertain significance in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-25). AlphaMissense: likely benign (0.0665); Very rare (popmax 0.00434%, amr); Associated with AFF2-related disorder.

What condition is associated with AFF2 p.His820Arg (c.2459A>G)?

AFF2 p.His820Arg (c.2459A>G) is associated with AFF2-related disorder (ClinVar).

How common is AFF2 p.His820Arg (c.2459A>G) in the general population?

AFF2 p.His820Arg (c.2459A>G) is very rare (popmax 0.00434%, amr) (gnomAD).

What do computational predictors say about AFF2 p.His820Arg (c.2459A>G)?

AlphaMissense predicts likely benign (score 0.0665) — an in-silico prediction, not a clinical call.

AFF2 p.His820Arg

c.2459A>G · rs782334806 · VCV2636273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0665 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00434%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AFF2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0665	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -5.25	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 1.3	GERP -2.5, phastCons 0.01
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	14.88	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 0.00434% Admixed American · 2/46,091 alleles

Filtering AF 0.000719% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000269%

Overall 0.000911% 10/1,098,117 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00434%	23,046
Remaining individualsnot grpmax-eligible	0.0021%	47,653
European (non-Finnish)	0.000782%	127,933

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: AFF2
Protein: p.His820Arg
Coding: c.2459A>G
MANE Select: NM_002025
dbSNP: rs782334806
Type: single nucleotide variant
Location: chrX:148956504 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 820: the 'disordered' region

Full AFF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AFF2-related disorder

Similar variants

AFF2 p.Asn687Asp Uncertain significance ⚠ same condition
AFF2 p.Ile360Val Uncertain significance ⚠ same condition
AFF2 p.Arg1115= Likely benign same condition
AFF2 p.Gln297= Likely benign same condition
AFF2 p.Thr1011= Likely benign same condition
AFF2 p.Tyr1181= Likely benign same condition
AFF2 c.1041+56452_1041+56454del Uncertain significance ★ same condition
AFF2 c.3267+5G>C 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/aff2-p-his820arg (accessed [today's date]).

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