Is AFF4 p.Ala489Val (c.1466C>T) pathogenic?

AFF4 p.Ala489Val (c.1466C>T) is classified Uncertain significance in AFF4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-17). AlphaMissense: ambiguous (0.3498); Very rare (popmax 0.00144%, nfe); Associated with AFF4-related disorder.

What condition is associated with AFF4 p.Ala489Val (c.1466C>T)?

AFF4 p.Ala489Val (c.1466C>T) is associated with AFF4-related disorder (ClinVar).

How common is AFF4 p.Ala489Val (c.1466C>T) in the general population?

AFF4 p.Ala489Val (c.1466C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about AFF4 p.Ala489Val (c.1466C>T)?

AlphaMissense predicts ambiguous (score 0.3498) — an in-silico prediction, not a clinical call.

AFF4 p.Ala489Val

c.1466C>T · VCV3353095

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3498 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

AFF4-related disorder

Computational evidence

Protein change
AlphaMissense	0.3498	ambiguous
REVEL	0.255	benign-leaning
SaProt	LLR -6.58	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 5.6, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 86 bp · p 4.6e-06 · regional, not allelic
Overall
CADD	27.5	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 0.00144% European (non-Finnish) · 17/1,180,026 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00116% 17/1,461,890 alleles · very rare

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.Ala489Val
Coding: c.1466C>T
MANE Select: NM_014423
Type: single nucleotide variant
Location: chr5:132897164 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 489: the 'disordered' region

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

Disease context

AFF4-related disorder

Similar variants

AFF4 p.Ala489= Likely benign same residue
AFF4 p.Ala489Thr Uncertain significance ★★ ⚠ same residue
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

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-ala489val (accessed [today's date]).

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