AIFM3

Chr 22

AIF family member 3

Also known as: AIFL

NCBI Gene: 150209ENSG00000183773UniProt: Q96NN9OMIM: 617298

The protein functions as an oxidoreductase that induces apoptosis through a caspase-dependent pathway and reduces mitochondrial membrane potential. Mutations in AIFM3 cause autosomal recessive severe combined immunodeficiency, typically presenting in infancy with recurrent severe infections due to profound T-cell lymphopenia. The disease primarily affects the immune system, leading to life-threatening opportunistic infections if untreated.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 0.99
Clinical Summary— AIFM3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
103 unique Pathogenic / Likely Pathogenic· 81 VUS of 200 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.99LOEUF
pLI 0.000
Z-score 1.61
OE 0.72 (0.53–0.99)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.00Z-score
OE missense 0.86 (0.78–0.94)
329 obs / 384.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.72 (0.53–0.99)
0≤0.351.4
Missense OE0.86 (0.78–0.94)
0≤0.61.4
Synonymous OE0.99
0≤1.21.6
LoF obs/exp: 27 / 37.7Missense obs/exp: 329 / 384.0Syn Z: 0.12
DN
0.6840th %ile
GOF
0.6150th %ile
LOF
0.3452th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic88
Likely Pathogenic15
VUS81
Likely Benign1
88
Pathogenic
15
Likely Pathogenic
81
VUS
1
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
88
0
88
Likely Pathogenic
0
0
15
0
15
VUS
0
56
25
0
81
Likely Benign
0
1
0
0
1
Benign
0
0
0
0
0
Total0571280185

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

AIFM3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical implications of a novel prognostic factor AIFM3 in breast cancer patients.
Zheng A et al.·BMC Cancer
2019Cohort
Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance.
Woodward KJ et al.·Mol Genet Genomic Med
2019Case report
Unveiling immune-metabolic interaction in Atherosclerosis via Comprehensive Landscape of Hub Genes and Immune Microenvironment.
Liu F et al.·Heart Surg Forum
2023
Knockdown of integrin β1 inhibits proliferation and promotes apoptosis in bladder cancer cells.
Wang JF et al.·Biofactors
2025
MLPA analysis of 32 foetuses with a congenital heart defect and 1 foetus with renal defects - pilot study. The significant frequency rate of presented pathological CNV.
Stefekova A et al.·Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub
2022
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Expression Pattern of AIFM3, VGLL4, and WNT4 in Patients with Different Stages of Colorectal Cancer.
Bevanda D et al.·Cancers (Basel)
2025Open AccessCohort
Bioinformatic Prediction of Novel Signaling Pathways of Apoptosis-inducing Factor, Mitochondrion-associated 3 (AIFM3) and Their Roles in Metastasis of Cholangiocarcinoma Cells.
Chua-On D et al.·Cancer Genomics Proteomics
2022
CRKL, AIFM3, AIF, BCL2, and UBASH3A during Human Kidney Development.
Lozic M et al.·Int J Mol Sci
2021Open Access
Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma.
Araujo AN et al.·Cancers (Basel)
2021Open Access
Apoptosis-Inducing Factor, Mitochondrion-Associated 3 (AIFM3) Protein Level in the Sera as a Prognostic Marker of Cholangiocarcinoma Patients.
Chua-On D et al.·Biomolecules
2020Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients