S100A12

Chr 1

S100 calcium binding protein A12

Also known as: CAAF1, CAGC, CGRP, ENRAGE, MRP-6, MRP6, p6

NCBI Gene: 6283 ENSG00000163221 UniProt: P80511

The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein is proposed to be involved in specific calcium-dependent signal transduction pathways and its regulatory effect on cytoskeletal components may modulate various neutrophil activities. The protein includes an antimicrobial peptide which has antibacterial activity. [provided by RefSeq, Nov 2014]

Research

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.44

Clinical Summary— S100A12

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.00) despite low pLI — interpret in context.

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ClinVar Variants

17 VUS of 23 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 →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.44LOEUF

pLI 0.482

Z-score 1.24

OE 0.00 (0.00–1.44)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.58Z-score

OE missense 1.23 (1.00–1.53)

60 obs / 48.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.00 (0.00–1.44)

0≤0.351.4

Missense OE?1.23 (1.00–1.53)

0≤0.61.4

Synonymous OE?1.37

0≤1.21.6

LoF obs/exp: 0 / 1.8Missense obs/exp: 60 / 48.6Syn Z: -1.28

This gene — mechanism propensity

0.84top 10%

GOF

0.87top 5%

LOF

0.2092th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

23 submitted variants in ClinVar

ClinVar

Classification Summary

VUS17

Likely Benign2

Benign1

VUS

Likely Benign

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	17	0	17
Likely Benign	2	0	2
Benign	0	1	1
Total	19	1	20

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap S100A12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →