Is AFF4 p.Leu74Phe (c.220C>T) pathogenic?

AFF4 p.Leu74Phe (c.220C>T) is classified Uncertain significance in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.1289); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with AFF4 p.Leu74Phe (c.220C>T)?

AFF4 p.Leu74Phe (c.220C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFF4 p.Leu74Phe (c.220C>T) in the general population?

AFF4 p.Leu74Phe (c.220C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFF4 p.Leu74Phe (c.220C>T)?

AlphaMissense predicts likely benign (score 0.1289) — an in-silico prediction, not a clinical call.

AFF4 p.Leu74Phe

c.220C>T · rs746481780 · VCV3092725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1289 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1289	likely benign
REVEL	0.416	indeterminate
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 4.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 2,298 bp · p 2e-05 · regional, not allelic
Overall
CADD	25.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFF4
Protein: p.Leu74Phe
Coding: c.220C>T
MANE Select: NM_014423
dbSNP: rs746481780
Type: single nucleotide variant
Location: chr5:132934845 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB

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-leu74phe (accessed [today's date]).

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