Is AFF3 p.His452Asp (c.1354C>G) pathogenic?

AFF3 p.His452Asp (c.1354C>G) is classified Likely benign in AFF3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely benign (0.1905); Ultra-rare (popmax 0.0426%, nfe); Associated with AFF3-related disorder.

What condition is associated with AFF3 p.His452Asp (c.1354C>G)?

AFF3 p.His452Asp (c.1354C>G) is associated with AFF3-related disorder (ClinVar).

How common is AFF3 p.His452Asp (c.1354C>G) in the general population?

AFF3 p.His452Asp (c.1354C>G) is ultra-rare (popmax 0.0426%, nfe) (gnomAD).

What do computational predictors say about AFF3 p.His452Asp (c.1354C>G)?

AlphaMissense predicts likely benign (score 0.1905) — an in-silico prediction, not a clinical call.

AFF3 p.His452Asp

c.1354C>G · VCV3357793

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0426%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AFF3-related disorder

Computational evidence

Protein change
AlphaMissense	0.1905	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -5.62	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 413 kb · p 0.58 · regional, not allelic
Overall
CADD	27.2	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 0.0426% European (non-Finnish) · 501/1,176,038 alleles

Filtering AF 0.0395% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.0331% 532/1,606,690 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0426%	2,347
Remaining individualsnot grpmax-eligible	0.0177%	5,646
Middle Eastern	0.0165%	6,048
East Asian	0.0112%	8,932
Admixed American	0.0101%	9,912
African / African-American	0.00936%	10,688
South Asian	0.00111%	89,946

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.His452Asp
Coding: c.1354C>G
MANE Select: NM_001386135
Type: single nucleotide variant
Location: chr2:99601452 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 452: the 'disordered' region

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

Disease context

AFF3-related disorder

Similar variants

AFF3 p.Met238Arg Likely pathogenic ★ ⚠ same condition
AFF3 p.His211Asn Uncertain significance ★ ⚠ same condition
AFF3 p.His889Gln Uncertain significance ★ ⚠ same condition
AFF3 p.Lys271Thr Uncertain significance ★ ⚠ same condition
AFF3 p.Pro332Thr Uncertain significance ★ ⚠ same condition
AFF3 p.Ala203Ser Uncertain significance ⚠ same condition
AFF3 c.2591+5G>A Benign same condition
AFF3 c.922-10C>T Benign 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-his452asp (accessed [today's date]).

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