Is AFF4 p.Ser491= (c.1473A>G) pathogenic?

AFF4 p.Ser491= (c.1473A>G) is classified Likely benign in AFF4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-08-12). Very rare (popmax 0.00534%, afr); Associated with AFF4-related disorder.

What condition is associated with AFF4 p.Ser491= (c.1473A>G)?

AFF4 p.Ser491= (c.1473A>G) is associated with AFF4-related disorder (ClinVar).

How common is AFF4 p.Ser491= (c.1473A>G) in the general population?

AFF4 p.Ser491= (c.1473A>G) is very rare (popmax 0.00534%, afr) (gnomAD).

AFF4 p.Ser491=

c.1473A>G · VCV3355877

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

AFF4-related disorder

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 1.5	GERP -3.7, phastCons 1
Overall
CADD	8.917	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,936 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000372% 6/1,614,110 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,734
European (non-Finnish)	0.000169%	590,019

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.Ser491=
Coding: c.1473A>G
MANE Select: NM_014423
Type: single nucleotide variant
Location: chr5:132897157 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 491: the 'disordered' region; a modified residue (phosphoserine)

Full AFF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

AFF4-related disorder

Similar variants

AFF4 p.Glu657Asp Uncertain significance ★★ ⚠ same condition
AFF4 p.Ser839Cys Uncertain significance ★★ ⚠ same condition
AFF4 p.Ala551Thr Uncertain significance ★ ⚠ same condition
AFF4 p.Arg209Ser Uncertain significance ★ ⚠ same condition
AFF4 p.Arg725Lys Uncertain significance ★ ⚠ same condition
AFF4 p.Asp422Gly Uncertain significance ★ ⚠ same condition
AFF4 p.Pro611Leu Uncertain significance ★ ⚠ same condition
AFF4 p.Ser1077Phe 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-ser491 (accessed [today's date]).

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