TAFA4

Chr 3

TAFA chemokine like family member 4

Also known as: FAM19A4, TAFA-4

NCBI Gene: 151647 ENSG00000163377 UniProt: Q96LR4 OMIM: 617498

This gene encodes a small secreted protein that functions as a brain-specific chemokine, modulating pain hypersensitivity and acting as a ligand for FPR1 to chemoattract macrophages and promote phagocytosis. TAFA4 mutations cause autosomal recessive inflammatory pain insensitivity, a rare disorder characterized by reduced sensitivity to painful stimuli due to impaired pain signaling pathways. The gene shows low constraint to loss-of-function variation (pLI 0.0007, LOEUF 1.3), consistent with recessive inheritance where both copies must be affected to cause disease.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the TAFA family which is composed of five highly homologous genes that encode small secreted proteins. These proteins contain conserved cysteine residues at fixed positions, and are distantly related to MIP-1alpha, a member of the CC-chemokine family. The TAFA proteins are predominantly expressed in specific regions of the brain, and are postulated to function as brain-specific chemokines or neurokines, that act as regulators of immune and nervous cells. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Nov 2011]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.29

Clinical Summary— TAFA4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

42 VUS of 47 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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?

1.29LOEUF

pLI 0.001

Z-score 0.97

OE 0.65 (0.36–1.29)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.11Z-score

OE missense 1.03 (0.87–1.23)

91 obs / 88.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.65 (0.36–1.29)

0≤0.351.4

Missense OE?1.03 (0.87–1.23)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 6 / 9.2Missense obs/exp: 91 / 88.1Syn Z: -0.97

This gene — mechanism propensity

0.6355th %ile

GOF

0.4973th %ile

LOF

0.4136th %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

47 submitted variants in ClinVar

ClinVar

Classification Summary

VUS42

Benign1

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	42	0	42
Likely Benign	0	0	0
Benign	0	1	1
Total	42	1	43

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap TAFA4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →