S100A4

Chr 1

S100 calcium binding protein A4

Also known as: 18A2, 42A, CAPL, FSP1, MTS1, P9KA, PEL98

NCBI Gene: 6275 ENSG00000196154 UniProt: P26447 OMIM: 114210

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 may function in motility, invasion, and tubulin polymerization. Chromosomal rearrangements and altered expression of this gene have been implicated in tumor metastasis. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.86

Clinical Summary— S100A4

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

7 VUS of 16 total submissions

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Clinical Trials

1 active or recruiting trial — 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?

1.86LOEUF

pLI 0.006

Z-score -0.04

OE 1.02 (0.44–1.86)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.36Z-score

OE missense 0.86 (0.68–1.10)

48 obs / 55.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.02 (0.44–1.86)

0≤0.351.4

Missense OE?0.86 (0.68–1.10)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 3 / 2.9Missense obs/exp: 48 / 55.7Syn Z: 0.70

This gene — mechanism propensity

0.83top 10%

GOF

0.86top 5%

LOF

0.2387th %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

16 submitted variants in ClinVar

ClinVar

Classification Summary

VUS7

Benign4

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	7	0	7
Likely Benign	0	0	0
Benign	0	4	4
Total	7	4	11

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap S100A4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →