Is AFF2 p.His664= (c.1992T>C) pathogenic?

AFF2 p.His664= (c.1992T>C) is classified Likely benign in AFF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-01). Rare (popmax 0.43%, eas).

How common is AFF2 p.His664= (c.1992T>C) in the general population?

AFF2 p.His664= (c.1992T>C) is rare (popmax 0.43%, eas) (gnomAD).

AFF2 p.His664=

c.1992T>C · rs201552726 · VCV2661607

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.43%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.14	GERP 0.54, phastCons 0.7
Overall
CADD	1.678	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.43% East Asian · 145/33,735 alleles

Filtering AF 0.373% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.351%

Overall 0.0126% 152/1,209,056 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.43%	233
Remaining individualsnot grpmax-eligible	0.0147%	6,802

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.His664=
Coding: c.1992T>C
MANE Select: NM_002025
dbSNP: rs201552726
Type: single nucleotide variant
Location: chrX:148956037 (GRCh38)
Structure: AlphaFold pLDDT 49.27
Residue 664: the 'disordered' region

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

Similar variants

AFF2 p.His664Leu Uncertain significance ★ ⚠ same residue
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

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-his664 (accessed [today's date]).

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