Is AFF4 p.Gln537Leu (c.1610A>T) pathogenic?

AFF4 p.Gln537Leu (c.1610A>T) is classified Uncertain significance in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-18). AlphaMissense: likely benign (0.1132); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFF4 p.Gln537Leu (c.1610A>T)?

AFF4 p.Gln537Leu (c.1610A>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFF4 p.Gln537Leu (c.1610A>T) in the general population?

AFF4 p.Gln537Leu (c.1610A>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AFF4 p.Gln537Leu (c.1610A>T)?

AlphaMissense predicts likely benign (score 0.1132) — an in-silico prediction, not a clinical call.

AFF4 p.Gln537Leu

c.1610A>T · VCV3840240

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1132	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -6.47	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 5.1	GERP 5.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 518 bp · p 0.026 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,938 alleles

Overall 0.000657% 1/152,218 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.Gln537Leu
Coding: c.1610A>T
MANE Select: NM_014423
Type: single nucleotide variant
Location: chr5:132897020 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 537: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFF4 p.Ala27Thr Uncertain significance ★★ ⚠ same condition
AFF4 p.Ala489Thr Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg153His Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg225His Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg3Cys Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg531Gln Uncertain significance ★★ ⚠ same condition
AFF4 p.Arg711Thr Uncertain significance ★★ ⚠ same condition
AFF4 p.Asn762Ser 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-gln537leu (accessed [today's date]).

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