Is AFF2 p.Arg597His (c.1790G>A) pathogenic?

AFF2 p.Arg597His (c.1790G>A) is classified Likely benign in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely benign (0.1252); Ultra-rare (popmax 0.0197%, amr).

How common is AFF2 p.Arg597His (c.1790G>A) in the general population?

AFF2 p.Arg597His (c.1790G>A) is ultra-rare (popmax 0.0197%, amr) (gnomAD).

What do computational predictors say about AFF2 p.Arg597His (c.1790G>A)?

AlphaMissense predicts likely benign (score 0.1252) — an in-silico prediction, not a clinical call.

AFF2 p.Arg597His

c.1790G>A · VCV4084482

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1252 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1252	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -0.9, phastCons 0.7
Regional constraint	o/e 0.94	unconstrained · MANE · 304 kb · p 0.17 · regional, not allelic
Overall
CADD	23.5	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 0.0197% Admixed American · 9/45,717 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00767%

Overall 0.00397% 48/1,209,600 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0197%	5,080
Remaining individualsnot grpmax-eligible	0.0063%	15,862
European (non-Finnish)	0.0038%	26,330
African / African-American	0.00351%	28,479

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.Arg597His
Coding: c.1790G>A
MANE Select: NM_002025
Type: single nucleotide variant
Location: chrX:148955835 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 597: the 'disordered' region

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

Similar variants

AFF2 c.3267+5G>C Uncertain significance ★★ same type
AFF2 p.Ala1197Thr Uncertain significance ★★ ⚠ same type
AFF2 p.Ala171Pro Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1238Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg1295Cys Uncertain significance ★★ ⚠ same type
AFF2 p.Arg670His Uncertain significance ★★ ⚠ same type
AFF2 p.Asn77Ile Uncertain significance ★★ ⚠ same type
AFF2 p.Asp187Glu 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-arg597his (accessed [today's date]).

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